{"gene":"CTCFL","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2002,"finding":"CTCFL/BORIS is a paralog of CTCF sharing the same 11-zinc-finger DNA-binding domain (encoded by identical exons) but with distinct amino and carboxy termini; it is expressed exclusively in testis in a mutually exclusive pattern with CTCF during male germ cell development, coinciding with erasure of methylation marks during epigenetic reprogramming.","method":"Molecular cloning, sequence analysis, Northern/Western blot, expression profiling in testis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — original cloning and characterization with multiple orthogonal methods; independently replicated across many subsequent studies","pmids":["12011441"],"is_preprint":false},{"year":2002,"finding":"Overexpression of BORIS in normally BORIS-negative somatic cells promotes cell growth and can lead to transformation, whereas CTCF overexpression blocks cell proliferation, demonstrating antagonistic functional roles.","method":"Ectopic expression in somatic cell lines, cell proliferation assays","journal":"Seminars in cancer biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay, single lab, confirmed in subsequent studies","pmids":["12191639"],"is_preprint":false},{"year":2005,"finding":"Conditional expression of BORIS in normal fibroblasts causes switching from CTCF to BORIS occupancy at an 11ZF target site in the MAGE-A1 promoter (a site insensitive to CpG methylation), leading to demethylation and transcriptional activation of MAGE-A1 and other cancer-testis genes; anti-BORIS shRNA prior to 5-azadC treatment blocked MAGE-A1 reactivation.","method":"Conditional BORIS expression, ChIP, bisulfite sequencing, shRNA knockdown, reporter assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP, shRNA rescue, multiple orthogonal methods; replicated in parallel study (PMID:16140944)","pmids":["16140943"],"is_preprint":false},{"year":2005,"finding":"BORIS binds a novel CTCF/BORIS-binding site in the NY-ESO-1 promoter (insensitive to CpG methylation in vitro); in vivo, CTCF occupancy correlates with NY-ESO-1 silencing while switching from CTCF to BORIS occupancy coincides with NY-ESO-1 derepression in lung cancer cells.","method":"Gel-shift assay, ChIP, bisulfite sequencing, methylation-specific PCR, co-transfection reporter assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (EMSA, ChIP, reporter); replicated with complementary study (PMID:16140943)","pmids":["16140944"],"is_preprint":false},{"year":2006,"finding":"CTCFL/BORIS interacts with PRMT7 (a protein arginine methyltransferase) and stimulates PRMT7's histone-methyltransferase activity via interactions with both histones and PRMT7; symmetrical dimethyl arginine 3 of histone H4 (catalyzed by PRMT7) accumulates in germ cells during ICR methylation. Nuclear co-injection of CTCFL, PRMT7, Dnmt3a, Dnmt3b, and DnmtL expression vectors in Xenopus oocytes was sufficient to drive H19 ICR methylation.","method":"Co-immunoprecipitation, in vitro histone methyltransferase assay, ChIP, Xenopus oocyte co-injection","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with reconstitution in Xenopus oocytes, multiple orthogonal methods in single study","pmids":["17048991"],"is_preprint":false},{"year":2007,"finding":"BORIS expression is regulated by three alternative promoters (A, B, C) that are negatively regulated by DNA methylation and by functional p53; reduction of CTCF in normally BORIS-negative fibroblasts leads to derepression of BORIS promoters, establishing CTCF as a transcriptional repressor of BORIS.","method":"5' RACE, promoter-reporter assays, bisulfite sequencing, CTCF knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter dissection with multiple methods, single lab","pmids":["17962299"],"is_preprint":false},{"year":2007,"finding":"BORIS physically interacts with Sp1 (but not with CTCF) in vivo, and BORIS recruits Sp1 to the proximal Sp1-binding site of the NY-ESO-1 promoter to mediate its derepression in lung cancer cells.","method":"Co-immunoprecipitation, ChIP, gel-shift assay, siRNA knockdown, promoter-reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus ChIP, single lab","pmids":["17260018"],"is_preprint":false},{"year":2008,"finding":"CTCFL/BORIS is a methylation-independent DNA-binding protein; ChIP and EMSA using whole-cell extracts and in vitro translated protein showed BORIS binds methylated DNA while CTCF preferentially binds unmethylated DNA. In murine hybrid cells, BORIS preferentially binds the methylated paternal H19 differentially methylated region.","method":"ChIP, EMSA with in vitro translated protein, methylation-specific ChIP-PCR, murine hybrid cell system","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro translated protein EMSA plus allele-specific ChIP, multiple orthogonal methods in single study","pmids":["18632606"],"is_preprint":false},{"year":2008,"finding":"DNA methyltransferases DNMT1 and DNMT3B activate BAG-1 expression by recruiting CTCFL/BORIS to the BAG-1 promoter, which is associated with a permissive dimethyl-H3K4/dimethyl-H3K9 chromatin state; BORIS shRNA knockdown decreased BORIS promoter binding and BAG-1 expression and shifted the chromatin to a non-permissive state.","method":"ChIP, shRNA knockdown, DNMT-overexpressing and knockout cell lines","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with shRNA functional validation, single lab","pmids":["18413740"],"is_preprint":false},{"year":2010,"finding":"BORIS binds to and activates the testis-specific CST (Gal3st1 form F_TS) promoter; mutation of the BORIS binding site in the promoter abrogated BORIS binding and activation. BORIS knockout mice showed reduced CST expression, delayed haploid cell production, and increased germ cell death.","method":"BORIS knockout mice, gene expression profiling, ChIP, promoter-reporter assay with binding site mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO mouse phenotype combined with ChIP and mutagenesis-based promoter assay","pmids":["20231363"],"is_preprint":false},{"year":2010,"finding":"Exogenous BORIS expression in normal BORIS-negative cells is sufficient to activate hTERT transcription; both CTCF and BORIS bind the first exon of hTERT in vivo in cancer cells, and BORIS counteracts the inhibitory effect of CTCF on hTERT.","method":"Ectopic BORIS expression, ChIP, quantitative RT-PCR","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional overexpression, single lab","pmids":["20876690"],"is_preprint":false},{"year":2010,"finding":"BORIS is expressed as 23 isoforms with alternative N- and C-termini and varying zinc finger numbers; all isoforms are translated and localize to the nucleus. Binding to DNA targets is methylation-sensitive and depends on the number and composition of zinc fingers; a specific long N-terminus (N258) combined with DNA-binding ability is necessary and sufficient for transcriptional activation of CST.","method":"RT-PCR isoform characterization, western blot, nuclear localization assay, EMSA, reporter assays with isoform-specific constructs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple isoforms characterized with functional assays, single lab","pmids":["21079786"],"is_preprint":false},{"year":2011,"finding":"BORIS directly binds two conserved binding sites in the TSP50 promoter in a methylation-independent but nucleosome-occupancy-dependent manner and activates TSP50 transcription; mutation of binding sites abolished BORIS binding and promoter activation.","method":"ChIP, EMSA, promoter-reporter assay with binding site mutagenesis, DNase I sensitivity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding with mutagenesis plus ChIP and reporter assays, multiple orthogonal methods","pmids":["21659515"],"is_preprint":false},{"year":2011,"finding":"BORIS binds to the promoters of MAGEA2, MAGEA3, and MAGEA4 and activates their expression by inducing a shift to open chromatin; MAGEA3 activation involved promoter demethylation while MAGEA2 and MAGEA4 activation was independent of promoter demethylation.","method":"Doxycycline-inducible BORIS expression, ChIP, luciferase reporter assay, bisulfite sequencing, siRNA knockdown","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with ChIP and bisulfite sequencing, single lab","pmids":["21558405"],"is_preprint":false},{"year":2011,"finding":"BORIS binds to the intronic ferT promoter and is required for FerT expression in colorectal cancer cells; BORIS knockdown significantly decreases ferT expression and correlates with hypomethylation of the ferT promoter.","method":"ChIP, siRNA knockdown, bisulfite sequencing, RT-PCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional knockdown, single lab","pmids":["22223638"],"is_preprint":false},{"year":2012,"finding":"CTCFL is expressed only transiently in spermatogonia and preleptotene spermatocytes, colocalizing with CTCF; absence of CTCFL causes subfertility with partially penetrant testicular atrophy and reduced expression of testis-specific genes (Gal3st1, Prss50). CTCFL binds promoters with loosely assembled nucleosomes whereas CTCF favors sites with phased nucleosomes. An ES cell rescue assay shows CTCFL is functionally distinct from CTCF.","method":"Immunohistochemistry, live-cell fluorescence microscopy, CTCFL KO mice, genome-wide RNA expression, genome-wide ChIP-seq, ES cell rescue assay","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO mouse plus genome-wide binding analysis plus functional rescue assay with multiple orthogonal methods","pmids":["22709888"],"is_preprint":false},{"year":2012,"finding":"BORIS localizes to the nucleolus (within nucleolin core structure, adjacent to fibrillarin) and to interphase centrosomes in keratinocytes; endogenous BORIS is present at active transcription sites. Blocking cell cycle at S phase or causing DNA damage produces striking BORIS accumulation. Ectopic BORIS expression increases S-phase cells and causes genomic instability; BORIS shRNA inhibits RNA transcription and cell cycle progression.","method":"Immunofluorescence, nascent RNA labeling, live-cell GFP imaging, cell cycle analysis, shRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with live imaging plus functional KD phenotype, single lab","pmids":["22724006"],"is_preprint":false},{"year":2012,"finding":"Dose-dependent BORIS expression induces SBSN activation at low concentrations via CpG island demethylation and chromatin opening at the SBSN TSS, while higher BORIS concentrations suppress SBSN via chromatin repression; increasing BORIS also reduces cell growth and colony formation in a dose-dependent manner.","method":"Doxycycline-inducible BORIS expression, bisulfite sequencing, ChIP, RT-PCR, colony formation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible dose-response system with ChIP and bisulfite sequencing, single lab","pmids":["22792300"],"is_preprint":false},{"year":2013,"finding":"Both BORIS and CTCF cause significant decrease in cell proliferation and clonogenic capacity and suppress breast cancer growth in an orthotopic model in vivo; both confer protective effects during UV-induced apoptosis in primary cells, challenging the simple oncogenic model for BORIS.","method":"Inducible lentiviral expression, cell proliferation assay, clonogenic assay, bioluminescent orthotopic mouse model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro plus in vivo functional assays, single lab","pmids":["23553099"],"is_preprint":false},{"year":2013,"finding":"BORIS/CTCFL is an RNA-binding protein; it associates with mRNA in neural stem cells and neurons, and co-fractionates with actively translating polysomes. The majority of BORIS-associated transcripts differ between cell types. BORIS contains a putative nuclear export signal in the C-terminal domain.","method":"RNA immunoprecipitation, polysome profiling, domain analysis","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP plus polysome profiling, single lab","pmids":["24279897"],"is_preprint":false},{"year":2014,"finding":"BORIS and Sp1 have opposing effects on MAGE-A1 promoter activity; both BORIS and Sp1 interact with the TATA-binding protein (hTBP), suggesting competitive regulation. Sp1 partially represses BORIS-mediated stimulation of the MAGE-A1 promoter. Ectopic BORIS also activates transcription from its own locus, inducing all splice variants.","method":"Luciferase reporter assays, ChIP, GST pull-down, quantitative RT-PCR, bisulfite sequencing","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down plus reporter assays with ChIP, single lab","pmids":["25363021"],"is_preprint":false},{"year":2015,"finding":"CTCFL and CTCF co-occupy a specific subset of regulatory elements with clustered CTCF binding motifs (2xCTSes); 2xCTSes are preferentially found at active promoters and enhancers in cancer and germ cells. BORIS depletion in K562 cells alters transcription of many genes and induces differentiation; ectopic BORIS in MCF7 cells induces specific transcriptional changes.","method":"Genome-wide ChIP-seq, BORIS depletion (siRNA/shRNA), ectopic expression, gene expression profiling","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with functional loss- and gain-of-function experiments, independently expanded in subsequent studies","pmids":["26268681"],"is_preprint":false},{"year":2016,"finding":"BORIS binds preferentially to the VNTR region of SVA transposable elements in vivo (distinct from CTCF binding to the CTCF motif); RNA-seq shows BORIS largely represses SVA expression alongside DNA and histone methylation, with exception of promoter capture by SVA.","method":"ChIP-chip, ChIP-seq, RNA-seq","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq plus RNA-seq, single lab","pmids":["27588042"],"is_preprint":false},{"year":2017,"finding":"Intragenic DNA methylation at the PKM alternative exon enables BORIS binding, which promotes cancer-specific PKM2 splicing and the Warburg effect; BORIS depletion or deletion of the BORIS binding site by CRISPR/Cas9 switches splicing from PKM2 to PKM1, reversing the Warburg effect and inhibiting breast cancer cell growth. BORIS also regulates alternative splicing of several other genes in a DNA methylation-dependent manner.","method":"BORIS depletion (siRNA), CRISPR/Cas9 binding site deletion, RT-PCR for splicing isoforms, metabolic assays, cell growth assays, bisulfite sequencing","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR deletion plus siRNA knockdown plus metabolic readout, multiple orthogonal methods","pmids":["29073069"],"is_preprint":false},{"year":2017,"finding":"BORIS binds near the TGFB1 promoter, coinciding with increased TGFB1 expression, and promotes a switch from a proliferative to an invasive phenotype in melanoma cells; inducible BORIS overexpression reduces proliferation and increases migration and invasion.","method":"Inducible BORIS overexpression, whole-transcriptome analysis (RNA-seq), ChIP, migration/invasion assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional assays with transcriptome analysis, single lab","pmids":["32123577"],"is_preprint":false},{"year":2017,"finding":"BORIS up-regulates OCT4 via histone methylation: BORIS binding at the OCT4 promoter increases H3K4me2 and reduces H3K27me3, without affecting DNA methylation at the OCT4 promoter. BORIS overexpression promotes cancer stem cell-like properties in liver cancer cells.","method":"ChIP, bisulfite sequencing, BORIS overexpression and knockdown, sphere formation and tumor-initiating assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for histone marks plus functional assays, single lab","pmids":["28645561"],"is_preprint":false},{"year":2017,"finding":"BORIS activates the TGFB1 pathway in neuroblastoma; BORIS stabilizes SMAD3 and SMAD4 transcripts, and loss of BORIS abrogates both canonical and non-canonical TGFβ signaling. Ectopic BORIS expression also induces Drp1 phosphorylation (Ser616), promoting mitochondrial fission and a metabolic switch toward glycolysis.","method":"BORIS overexpression and knockdown, RT-PCR, western blot (pathway components), oxygen consumption rate measurement","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain- and loss-of-function with pathway readouts, single lab","pmids":["34534628"],"is_preprint":false},{"year":2018,"finding":"CTCFL binding site selection versus CTCF is driven by chromatin state: CTCFL is enriched at open chromatin marked by H3K27ac, H3K4me2/3, H3K79me2, H3K9ac, and H2A.Z, particularly at TSS regions. Specific nucleotide positions in the binding motif are critical for CTCFL but not CTCF binding.","method":"ChIP-seq, ATAC-seq, motif analysis, genome-wide binding comparison","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with chromatin state correlations, single lab","pmids":["29860503"],"is_preprint":false},{"year":2019,"finding":"BORIS promotes chromatin looping interactions in ALK-inhibitor-resistant, MYCN-amplified neuroblastoma cells; resistance is accompanied by loss of MYCN expression followed by BORIS overexpression. BORIS-regulated alterations in chromatin looping form super-enhancers that drive ectopic expression of proneural transcription factors defining the resistance phenotype.","method":"Hi-C/chromatin conformation capture, ChIP-seq, BORIS overexpression and depletion, RNA-seq, resistance model development","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide chromatin conformation plus ChIP-seq plus functional rescue in a rigorous resistance model","pmids":["31391581"],"is_preprint":false},{"year":2019,"finding":"BORIS expression in fallopian tube secretory epithelial cells (FTSEC) increases motility and invasion, and induces GALNT14 (a glycosyltransferase implicated in cancer cell migration); GALNT14 knockdown significantly abrogates BORIS-induced motility and invasion. BORIS expression is also associated with de novo and enhanced CTCF binding at hundreds of loci correlated with transcriptional activation.","method":"Lentiviral BORIS expression in FTSEC, migration/invasion assays, siRNA knockdown of GALNT14, RNA-seq, ChIP-seq","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis (GALNT14 KD rescue) plus ChIP-seq, single lab","pmids":["31292201"],"is_preprint":false},{"year":2019,"finding":"MAGEA1 interacts with CTCF to form a protein complex with DNMT3a; this complex binds the BORIS promoter, recruits DNMT3a, and causes hypermethylation and repression of BORIS expression. The MAGEA1-CTCF interaction is required for DNMT3a recruitment.","method":"Co-immunoprecipitation, GST pull-down, co-localization assay, ChIP, bisulfite sequencing, siRNA knockdown","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and GST pull-down plus ChIP and bisulfite sequencing, single lab","pmids":["30498011"],"is_preprint":false},{"year":2020,"finding":"The N-terminus of CTCF (not shared by CTCFL) interacts with cohesin, explaining why convergent CTCF binding sites are required for loop formation; CTCFL lacks this N-terminal cohesin interaction and therefore cannot mediate the same chromatin loops as CTCF. CTCF and CTCFL have phenotypically distinct binding sites; N, C, and zinc finger domains each play unique roles in targeting each paralog to distinct sites.","method":"Inducible complementation system expressing CTCFL and CTCF-CTCFL chimeras ± endogenous CTCF, ChIP-seq, Hi-C, RNA-seq","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain-swap chimera approach with genome-wide Hi-C and ChIP-seq in presence/absence of CTCF","pmids":["32393311"],"is_preprint":false},{"year":2021,"finding":"BORIS heterodimerizes with CTCF and combined depletion of both CTCF and BORIS (Ctcf+/-Boris-/- compound mutant mice) causes male sterility with reduced testes size, defective meiotic recombination, increased apoptosis, and malformed spermatozoa; chromatin binding of CTCF is preferentially lost from CTCF-BORIS heterodimeric sites. Combined action is required to repress pre-meiotic genes and activate post-meiotic spermatogenesis genes.","method":"Mouse genetic models (compound mutants with varied CTCF/BORIS levels), ChIP-seq, RNA-seq, fertility assays, histology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — rigorous genetic epistasis with compound mutant mice plus genome-wide ChIP-seq and RNA-seq","pmids":["34158481"],"is_preprint":false},{"year":2021,"finding":"CTCFL expression during mouse embryogenesis dysregulates the TGFβ pathway; transcriptome sequencing of Ctcfl-expressing ES cells revealed 14 deregulated genes with TGFβ pathway as most affected, and Ctcfl-expressing embryos show growth retardation, eye malformations, vascular defects, and neonatal death.","method":"Tetracycline-inducible transgenic mice, ES cell-tetraploid chimeras, RNA-seq, bioinformatic pathway analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible transgenic mouse model with transcriptome sequencing, single lab","pmids":["26169830"],"is_preprint":false},{"year":2022,"finding":"BORIS undergoes ADP ribosylation at five conserved glutamic acid residues (E198–E228) upon DNA double- or single-strand damage; this modification is required for BORIS interaction with Ku70 and for BORIS function in DNA damage repair. Inhibiting ADP ribosylation (by site-specific mutation or by BTApep-TAT peptide) blocks BORIS-Ku70 interaction and impairs DNA damage repair.","method":"Phage display peptide inhibitor (BTApep-TAT), site-directed mutagenesis, co-immunoprecipitation, γH2AX assay, RNA-seq, xenograft mouse model","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of PTM sites plus co-IP functional validation plus in vivo xenograft, multiple orthogonal methods","pmids":["35918747"],"is_preprint":false},{"year":2022,"finding":"HNF4A directly binds the BORIS promoter and negatively regulates BORIS expression; BORIS in turn directly binds the GLUT4 promoter and positively regulates GLUT4 expression, promoting hepatoma cell motility and metastasis in low-glucose conditions (AMPKα2/HNF4A/BORIS/GLUT4 pathway).","method":"ChIP, overexpression and knockdown complementation experiments, bioinformatic analysis, invasion/metastasis assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional epistasis experiments, single lab","pmids":["35940258"],"is_preprint":false},{"year":2024,"finding":"BORIS/CTCFL epigenetically reprograms intergenic and intronic CTCF binding sites (2xCTSes) into active de novo promoters by recruiting the chromatin remodeling factor SRCAP, causing replacement of H2A with H2A.Z and relaxation of flanking nucleosomes; this facilitates recruitment of additional transcription factors and activates cancer-testis gene expression, lncRNAs, retro-pseudogenes, and dormant transposable elements.","method":"ChIP-seq, ATAC-seq, RNA-seq, co-immunoprecipitation (BORIS-SRCAP interaction), H2A.Z ChIP, BORIS depletion and overexpression","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic reconstitution with co-IP of SRCAP, genome-wide chromatin remodeling assays, multiple orthogonal methods","pmids":["38297316"],"is_preprint":false},{"year":2024,"finding":"BORIS binds methylated BNIP3L intron 1 under normoxia (while CTCF binds unmethylated intron 1 under hypoxia); BORIS binding causes RNA Pol-II pausing and recruits SRSF6, redirecting proximal splice-site selection to exclude exon 1 from BNIP3L mRNA (generating BNIP3L-Δ1 isoform), thereby inhibiting autophagy.","method":"ChIP (CTCF, BORIS, RNA Pol-II), bisulfite sequencing, RT-PCR splicing assay, siRNA knockdown, SRSF6 interaction assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with bisulfite sequencing and functional splicing assays, single lab","pmids":["38810696"],"is_preprint":false},{"year":2017,"finding":"BORIS physically interacts with TBP-associated factor 7-like (TAF7L) in germ cells; BORIS-bound 2xCTS regions are co-occupied by multiple testis-specific transcriptional regulators and are associated with highly expressed germ cell-specific genes and histone retention in mature spermatozoa.","method":"Co-immunoprecipitation (BORIS-TAF7L), ChIP-seq in mouse germ cells, histone retention analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genome-wide ChIP-seq, single lab","pmids":["28145452"],"is_preprint":false},{"year":2008,"finding":"DNA damage-induced upregulation of miR-709 in mouse testis (via ATR/Rfx1 signaling) targets BORIS mRNA and decreases BORIS protein levels, acting as a protective mechanism to prevent aberrant erasure of DNA methylation after radiation exposure.","method":"MicroRNA microarray, quantitative RT-PCR, miR-709 target validation (BORIS 3'UTR targeting)","journal":"Cell cycle","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression-based target assignment with limited functional validation of BORIS as direct miR-709 target, single lab","pmids":["19029807"],"is_preprint":false},{"year":2010,"finding":"The C-terminal fragment of CTCFL predominantly consists of extended and disordered content by biophysical analysis; computational analysis predicts the N-terminal segment is also disordered, suggesting that sequence divergence in the unstructured terminal segments drives differential cofactor recruitment to distinguish CTCFL from CTCF.","method":"Biophysical characterization of recombinant C-terminal fragment (secondary structure analysis), computational disorder prediction","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — partial structural characterization without functional mutagenesis validation, single lab","pmids":["20438700"],"is_preprint":false},{"year":2012,"finding":"Rb2/p130 forms complexes with CTCF or BORIS under ER stress conditions in mouse medulloblastoma cells; T antigen induces chronic ER stress, associated with Caspase-12 activation and formation of Rb2/p130-CTCF or Rb2/p130-BORIS complexes as part of a non-canonical ER-dependent death pathway.","method":"Co-immunoprecipitation, western blot, cell death assays in T-Ag positive/negative medulloblastoma cell lines","journal":"Cell cycle","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP study with limited mechanistic follow-up, single lab","pmids":["22544282"],"is_preprint":false},{"year":2023,"finding":"Boris knockout in mice reduces incidence and severity of AOM/DSS-induced colorectal cancer; Boris KO promotes γH2AX phosphorylation and DNA damage in colorectal cancer tissues, and suppresses Wnt and MAPK signaling (which mediate DNA damage repair callback). Boris KO also alleviates DSS-induced colitis via inhibition of NF-κB signaling in macrophages.","method":"Boris knockout mice, AOM/DSS colorectal cancer model, γH2AX immunofluorescence, western blot (Wnt, MAPK, NF-κB pathway), DSS-colitis model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO mouse cancer model with pathway analysis, single lab","pmids":["36692143"],"is_preprint":false}],"current_model":"CTCFL/BORIS is a testis-specific paralog of CTCF sharing an identical 11-zinc-finger DNA-binding domain but with divergent N- and C-termini; it preferentially binds clustered CTCF target sites (2xCTSes) in a nucleosome-composition-dependent, largely methylation-independent manner, heterodimerizes with CTCF to cooperatively regulate spermatogenesis gene programs, and in cancer cells acts as a chromatin remodeler that recruits SRCAP to replace H2A with H2A.Z at CTCF sites, epigenetically converting them into active alternative promoters, while also regulating alternative splicing via DNA methylation-dependent binding at intragenic sites, interacting with PRMT7 to stimulate histone arginine methylation, associating with polysomes as an RNA-binding protein, and undergoing ADP ribosylation upon DNA damage to engage Ku70 in DNA damage repair."},"narrative":{"mechanistic_narrative":"CTCFL (BORIS) is a testis-restricted paralog of CTCF that shares an identical 11-zinc-finger DNA-binding domain encoded by the same exons but carries divergent N- and C-termini, and it is expressed in a mutually exclusive pattern with CTCF during male germ-cell epigenetic reprogramming [PMID:12011441]. Its terminal segments are intrinsically disordered, providing a structural basis for paralog-specific cofactor recruitment that distinguishes it from CTCF [PMID:20438700]. CTCFL and CTCF co-occupy a subset of clustered CTCF target sites (2xCTSes) found at active promoters and enhancers, and the two proteins act combinatorially to repress pre-meiotic genes and activate post-meiotic spermatogenesis programs; combined depletion in mice causes male sterility, defective meiotic recombination, and germ-cell death [PMID:26268681, PMID:34158481]. Site selection by CTCFL is governed by chromatin state rather than methylation: it is targeted to open chromatin marked by H3K27ac, H3K4me2/3 and H2A.Z and to loosely assembled nucleosomes, and unlike CTCF it lacks the N-terminal cohesin-interaction module required for canonical loop formation [PMID:22709888, PMID:29860503, PMID:32393311]. Mechanistically, CTCFL functions as a chromatin remodeler that recruits the SRCAP complex to exchange H2A for H2A.Z and relax flanking nucleosomes, converting intergenic and intronic CTCF sites into active de novo promoters that drive cancer-testis genes, lncRNAs, and dormant transposable elements [PMID:38297316]. It also stimulates PRMT7-catalyzed symmetric H4R3 dimethylation during germ-cell imprint establishment [PMID:17048991], and in cancer cells it reactivates silenced loci such as MAGE-A1 and NY-ESO-1 through a CTCF-to-BORIS occupancy switch and chromatin opening [PMID:16140943, PMID:16140944, PMID:21558405]. Beyond transcription, CTCFL binds intragenic methylated DNA to control alternative splicing—promoting cancer-specific PKM2 splicing and the Warburg effect—is an RNA-binding protein that co-fractionates with translating polysomes, and undergoes DNA-damage-induced ADP-ribosylation that recruits Ku70 for DNA damage repair [PMID:29073069, PMID:24279897, PMID:35918747]. In neuroblastoma it remodels chromatin looping to generate super-enhancers driving drug resistance [PMID:31391581].","teleology":[{"year":2002,"claim":"Established that CTCFL is a distinct, testis-specific CTCF paralog rather than a redundant copy, defining the central puzzle of two proteins sharing a DNA-binding domain but separated in space and time.","evidence":"Molecular cloning, sequence analysis, and testis expression profiling against CTCF","pmids":["12011441"],"confidence":"High","gaps":["Did not define genome-wide binding differences from CTCF","Mechanism of mutually exclusive expression not resolved"]},{"year":2002,"claim":"First evidence that CTCFL and CTCF have antagonistic effects on proliferation, framing CTCFL as a potential growth-promoting/transforming factor.","evidence":"Ectopic expression in somatic cell lines with proliferation assays","pmids":["12191639"],"confidence":"Medium","gaps":["No molecular mechanism for growth promotion","Later work (#18) challenged the simple oncogenic model"]},{"year":2005,"claim":"Showed that a CTCF-to-BORIS occupancy switch at methylation-insensitive 11ZF sites reactivates silenced cancer-testis genes (MAGE-A1, NY-ESO-1), linking paralog switching to epigenetic derepression.","evidence":"Conditional BORIS expression, reciprocal ChIP, bisulfite sequencing, shRNA rescue in fibroblasts and lung cancer cells","pmids":["16140943","16140944"],"confidence":"High","gaps":["Chromatin remodeling machinery recruited by BORIS not yet identified","Generality across the genome untested"]},{"year":2006,"claim":"Identified PRMT7 as a CTCFL cofactor, providing a histone-modification mechanism (symmetric H4R3 dimethylation) linking CTCFL to germline imprint establishment.","evidence":"Co-IP, in vitro histone methyltransferase assay, and Xenopus oocyte reconstitution of H19 ICR methylation","pmids":["17048991"],"confidence":"High","gaps":["Endogenous requirement for CTCFL-PRMT7 in mammalian imprinting not shown","Direct genomic targets of the complex undefined"]},{"year":2007,"claim":"Defined how BORIS is itself controlled, showing alternative promoters repressed by DNA methylation, p53, and CTCF, and identifying Sp1 as a recruited transcriptional partner at target promoters.","evidence":"5' RACE, promoter-reporter assays, CTCF knockdown, co-IP and ChIP for Sp1","pmids":["17962299","17260018"],"confidence":"Medium","gaps":["Single-lab promoter dissection","Sp1 interaction not tested genome-wide"]},{"year":2008,"claim":"Resolved the methylation question by showing BORIS binds methylated DNA (including the methylated paternal H19 DMR) while CTCF prefers unmethylated DNA, distinguishing the paralogs biochemically.","evidence":"EMSA with in vitro translated protein, methylation-specific and allele-specific ChIP in murine hybrid cells","pmids":["18632606"],"confidence":"High","gaps":["Reconciliation with methylation-insensitive sites (#2,#3) left open","Structural basis of methylated-DNA preference unknown"]},{"year":2010,"claim":"Linked BORIS to a germline gene program in vivo, showing it activates testis-specific genes and that its loss causes subfertility and germ-cell death.","evidence":"BORIS knockout mice, expression profiling, ChIP, and promoter mutagenesis for Gal3st1/CST","pmids":["20231363"],"confidence":"High","gaps":["Partial penetrance suggested redundancy not yet explained","Cofactors driving activation in vivo not identified"]},{"year":2010,"claim":"Demonstrated functional diversity of BORIS through 23 nuclear isoforms with variable zinc-finger composition, showing N-terminal identity and DNA binding jointly determine transcriptional activation.","evidence":"RT-PCR isoform characterization, EMSA, and isoform-specific reporter assays","pmids":["21079786"],"confidence":"Medium","gaps":["Physiological roles of individual isoforms unresolved","Single-lab characterization"]},{"year":2012,"claim":"Established chromatin-state, not methylation alone, as the determinant of CTCFL versus CTCF targeting, with CTCFL favoring loosely assembled nucleosomes and being functionally non-interchangeable with CTCF.","evidence":"CTCFL KO mice, genome-wide ChIP-seq, and ES-cell rescue assay","pmids":["22709888"],"confidence":"High","gaps":["Remodeler responsible for the loose-nucleosome state not yet identified","Mechanism of distinct site targeting incompletely defined"]},{"year":2012,"claim":"Connected BORIS to cell-cycle progression, transcription, and genomic instability, and localized it to nucleolus and centrosomes with accumulation upon S-phase arrest and DNA damage.","evidence":"Immunofluorescence, nascent RNA labeling, live-cell imaging, and shRNA knockdown in keratinocytes","pmids":["22724006"],"confidence":"Medium","gaps":["Centrosomal/nucleolar functions not mechanistically dissected","Link between DNA damage accumulation and repair not established here"]},{"year":2015,"claim":"Defined the genomic logic of paralog co-occupancy: CTCFL and CTCF share clustered 2xCTSes enriched at active promoters/enhancers, and BORIS perturbation reprograms transcription and differentiation.","evidence":"Genome-wide ChIP-seq with loss- and gain-of-function in K562 and MCF7 cells","pmids":["26268681"],"confidence":"High","gaps":["Mechanism converting 2xCTSes to active promoters not yet defined","Cofactor recruitment at 2xCTSes unknown"]},{"year":2017,"claim":"Extended BORIS function to co-transcriptional RNA processing, showing intragenic methylation-dependent binding controls cancer-specific PKM2 splicing and the Warburg effect.","evidence":"siRNA depletion, CRISPR/Cas9 binding-site deletion, splicing RT-PCR, and metabolic assays in breast cancer cells","pmids":["29073069"],"confidence":"High","gaps":["Splicing machinery recruited by BORIS not identified here","Breadth of methylation-dependent splicing targets only partly mapped"]},{"year":2017,"claim":"Identified TAF7L as a germ-cell-specific BORIS partner and placed BORIS-bound 2xCTSes at highly expressed germ-cell genes with histone retention in spermatozoa.","evidence":"Co-IP and ChIP-seq in mouse germ cells with histone-retention analysis","pmids":["28145452"],"confidence":"Medium","gaps":["Functional consequence of TAF7L interaction untested","Single-lab co-IP"]},{"year":2019,"claim":"Demonstrated that BORIS reshapes 3D chromatin to form super-enhancers, driving an ALK-inhibitor-resistance transcriptional program in MYCN-amplified neuroblastoma.","evidence":"Hi-C, ChIP-seq, RNA-seq, and overexpression/depletion in a resistance model","pmids":["31391581"],"confidence":"High","gaps":["Mechanism by which BORIS nucleates new loops without cohesin module unclear","Whether looping is direct or downstream of transcription not resolved"]},{"year":2020,"claim":"Pinpointed the molecular reason CTCFL cannot replace CTCF in loop formation: the CTCF N-terminus binds cohesin while CTCFL lacks it, with each domain contributing to paralog-specific targeting.","evidence":"Inducible complementation with CTCF-CTCFL chimeras, ChIP-seq, and Hi-C ± endogenous CTCF","pmids":["32393311"],"confidence":"High","gaps":["How CTCFL still promotes looping in some contexts (#28) not reconciled","Cofactors bound by the divergent CTCFL termini not fully enumerated"]},{"year":2021,"claim":"Showed CTCF and BORIS heterodimerize and act combinatorially to control the meiotic-to-postmeiotic gene switch, with loss of both causing sterility and CTCF binding lost preferentially from heterodimeric sites.","evidence":"Compound mutant mice with graded CTCF/BORIS levels, ChIP-seq, RNA-seq, fertility and histology","pmids":["34158481"],"confidence":"High","gaps":["Stoichiometry and structural basis of heterodimerization not defined","Direct versus indirect target effects not fully separated"]},{"year":2022,"claim":"Revealed a non-transcriptional role in genome maintenance: DNA-damage-induced ADP-ribosylation of conserved glutamates licenses BORIS-Ku70 interaction and DNA repair.","evidence":"Site-directed mutagenesis, peptide inhibitor (BTApep-TAT), co-IP, γH2AX assay, and xenograft model","pmids":["35918747"],"confidence":"High","gaps":["Identity of the ADP-ribosyltransferase not established","Repair pathway placement (NHEJ vs other) only inferred via Ku70"]},{"year":2024,"claim":"Delivered the unifying chromatin-remodeling mechanism: BORIS recruits SRCAP to deposit H2A.Z and relax nucleosomes, converting silent CTCF sites into active de novo promoters for cancer-testis genes and repeats.","evidence":"ChIP-seq, ATAC-seq, H2A.Z ChIP, RNA-seq, and BORIS-SRCAP co-IP with depletion/overexpression","pmids":["38297316"],"confidence":"High","gaps":["Whether SRCAP recruitment explains all BORIS-activated loci untested","Connection to the disordered termini (#40) not directly demonstrated"]},{"year":null,"claim":"How CTCFL integrates its multiple activities—chromatin remodeling, methylation-dependent splicing, RNA binding, and DNA-damage repair—into a single coherent cellular program, and how its divergent disordered termini route it among these functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking disordered termini to specific cofactor choices","Relative contribution of each activity to germ-cell versus cancer phenotypes unclear","No reconstitution of full SRCAP-dependent promoter conversion in vitro"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7,12,21,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,9,12,21,36]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[19]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,16]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[16]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[16]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[21,36,28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,21,36]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[23,37,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[34]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,9,32]}],"complexes":[],"partners":["CTCF","PRMT7","SRCAP","KU70","SP1","TAF7L","SRSF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NI51","full_name":"Transcriptional repressor CTCFL","aliases":["Brother of the regulator of imprinted sites","CCCTC-binding factor","CTCF paralog","CTCF-like protein","Cancer/testis antigen 27","CT27","Zinc finger protein CTCF-T"],"length_aa":663,"mass_kda":75.7,"function":"Testis-specific DNA binding protein responsible for insulator function, nuclear architecture and transcriptional control, which probably acts by recruiting epigenetic chromatin modifiers. Plays a key role in gene imprinting in male germline, by participating in the establishment of differential methylation at the IGF2/H19 imprinted control region (ICR). Directly binds the unmethylated H19 ICR and recruits the PRMT7 methyltransferase, leading to methylate histone H4 'Arg-3' to form H4R3sme2. This probably leads to recruit de novo DNA methyltransferases at these sites (By similarity). Seems to act as tumor suppressor. In association with DNMT1 and DNMT3B, involved in activation of BAG1 gene expression by binding to its promoter. Required for dimethylation of H3 lysine 4 (H3K4me2) of MYC and BRCA1 promoters","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8NI51/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTCFL","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CTCFL","total_profiled":1310},"omim":[{"mim_id":"607022","title":"CCCTC-BINDING FACTOR-LIKE PROTEIN; CTCFL","url":"https://www.omim.org/entry/607022"},{"mim_id":"604167","title":"CCCTC-BINDING FACTOR; CTCF","url":"https://www.omim.org/entry/604167"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":10.4}],"url":"https://www.proteinatlas.org/search/CTCFL"},"hgnc":{"alias_symbol":["dJ579F20.2","BORIS","CT27"],"prev_symbol":[]},"alphafold":{"accession":"Q8NI51","domains":[{"cath_id":"3.30.160.60","chopping":"485-568","consensus_level":"high","plddt":83.8614,"start":485,"end":568}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NI51","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NI51-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NI51-F1-predicted_aligned_error_v6.png","plddt_mean":54.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTCFL","jax_strain_url":"https://www.jax.org/strain/search?query=CTCFL"},"sequence":{"accession":"Q8NI51","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NI51.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NI51/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NI51"}},"corpus_meta":[{"pmid":"12011441","id":"PMC_12011441","title":"BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12011441","citation_count":285,"is_preprint":false},{"pmid":"12191639","id":"PMC_12191639","title":"The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer.","date":"2002","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/12191639","citation_count":215,"is_preprint":false},{"pmid":"17048991","id":"PMC_17048991","title":"The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation.","date":"2006","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/17048991","citation_count":162,"is_preprint":false},{"pmid":"16140943","id":"PMC_16140943","title":"Conditional expression of the CTCF-paralogous transcriptional factor BORIS in normal cells results in demethylation and derepression of MAGE-A1 and reactivation of other cancer-testis genes.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16140943","citation_count":162,"is_preprint":false},{"pmid":"16140944","id":"PMC_16140944","title":"Reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter coincides with derepression of this cancer-testis gene in lung cancer cells.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16140944","citation_count":154,"is_preprint":false},{"pmid":"18095639","id":"PMC_18095639","title":"DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer.","date":"2007","source":"Cancer immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18095639","citation_count":91,"is_preprint":false},{"pmid":"31391581","id":"PMC_31391581","title":"BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31391581","citation_count":86,"is_preprint":false},{"pmid":"17962299","id":"PMC_17962299","title":"Expression of the CTCF-paralogous cancer-testis gene, brother of the regulator of imprinted sites (BORIS), is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17962299","citation_count":82,"is_preprint":false},{"pmid":"26268681","id":"PMC_26268681","title":"Comparative analyses of CTCF and BORIS occupancies uncover two distinct classes of CTCF binding genomic regions.","date":"2015","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/26268681","citation_count":81,"is_preprint":false},{"pmid":"18195709","id":"PMC_18195709","title":"BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours.","date":"2008","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18195709","citation_count":79,"is_preprint":false},{"pmid":"22709888","id":"PMC_22709888","title":"The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner.","date":"2012","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/22709888","citation_count":74,"is_preprint":false},{"pmid":"21296871","id":"PMC_21296871","title":"Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: association with the BORIS/CTCF expression ratio and advanced stage.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/21296871","citation_count":69,"is_preprint":false},{"pmid":"16854382","id":"PMC_16854382","title":"Epigenetic control of CTCFL/BORIS and OCT4 expression in urogenital malignancies.","date":"2006","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16854382","citation_count":68,"is_preprint":false},{"pmid":"24983365","id":"PMC_24983365","title":"Circulating cell-free cancer-testis MAGE-A RNA, BORIS RNA, let-7b and miR-202 in the blood of patients with breast cancer and benign breast diseases.","date":"2014","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24983365","citation_count":66,"is_preprint":false},{"pmid":"18769711","id":"PMC_18769711","title":"The evolution of epigenetic regulators CTCF and BORIS/CTCFL in amniotes.","date":"2008","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18769711","citation_count":65,"is_preprint":false},{"pmid":"32334335","id":"PMC_32334335","title":"CTCF and CTCFL in cancer.","date":"2020","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/32334335","citation_count":64,"is_preprint":false},{"pmid":"20231363","id":"PMC_20231363","title":"Expression of a testis-specific form of Gal3st1 (CST), a gene essential for spermatogenesis, is regulated by the CTCF paralogous gene BORIS.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20231363","citation_count":63,"is_preprint":false},{"pmid":"29073069","id":"PMC_29073069","title":"Intragenic DNA methylation and BORIS-mediated cancer-specific splicing contribute to the Warburg effect.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29073069","citation_count":62,"is_preprint":false},{"pmid":"22019212","id":"PMC_22019212","title":"BORIS in human cancers -- a review.","date":"2011","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/22019212","citation_count":62,"is_preprint":false},{"pmid":"17260018","id":"PMC_17260018","title":"Dynamic transcriptional regulatory complexes including BORIS, CTCF and Sp1 modulate NY-ESO-1 expression in lung cancer cells.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17260018","citation_count":62,"is_preprint":false},{"pmid":"17363524","id":"PMC_17363524","title":"Global expression analysis of cancer/testis genes in uterine cancers reveals a high incidence of BORIS expression.","date":"2007","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17363524","citation_count":59,"is_preprint":false},{"pmid":"33599191","id":"PMC_33599191","title":"Exploring the cancer-testis antigen BORIS to design a novel multi-epitope vaccine against breast cancer based on immunoinformatics approaches.","date":"2021","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/33599191","citation_count":59,"is_preprint":false},{"pmid":"20876690","id":"PMC_20876690","title":"BORIS/CTCFL-mediated transcriptional regulation of the hTERT telomerase gene in testicular and ovarian tumor cells.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20876690","citation_count":55,"is_preprint":false},{"pmid":"21079786","id":"PMC_21079786","title":"The structural complexity of the human BORIS gene in gametogenesis and cancer.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21079786","citation_count":52,"is_preprint":false},{"pmid":"32393311","id":"PMC_32393311","title":"Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation.","date":"2020","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/32393311","citation_count":48,"is_preprint":false},{"pmid":"17957795","id":"PMC_17957795","title":"Expression of BORIS in melanoma: lack of association with MAGE-A1 activation.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17957795","citation_count":47,"is_preprint":false},{"pmid":"19029807","id":"PMC_19029807","title":"DNA damage-induced upregulation of miR-709 in the germline downregulates BORIS to counteract aberrant DNA hypomethylation.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19029807","citation_count":47,"is_preprint":false},{"pmid":"21558405","id":"PMC_21558405","title":"BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/21558405","citation_count":47,"is_preprint":false},{"pmid":"24657531","id":"PMC_24657531","title":"CTCF and BORIS in genome regulation and cancer.","date":"2013","source":"Current opinion in genetics & development","url":"https://pubmed.ncbi.nlm.nih.gov/24657531","citation_count":46,"is_preprint":false},{"pmid":"18467432","id":"PMC_18467432","title":"Differential expression of the embryo/cancer gene ECSA(DPPA2), the cancer/testis gene BORIS and the pluripotency structural gene OCT4, in human preimplantation development.","date":"2008","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18467432","citation_count":45,"is_preprint":false},{"pmid":"18355444","id":"PMC_18355444","title":"Selective apoptosis of breast cancer cells by siRNA targeting of BORIS.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18355444","citation_count":42,"is_preprint":false},{"pmid":"34848739","id":"PMC_34848739","title":"Immunoprotective effect of an in silico designed multiepitope cancer vaccine with BORIS cancer-testis antigen target in a murine mammary carcinoma model.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34848739","citation_count":41,"is_preprint":false},{"pmid":"23553099","id":"PMC_23553099","title":"The cancer-testis antigen BORIS phenocopies the tumor suppressor CTCF in normal and neoplastic cells.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23553099","citation_count":40,"is_preprint":false},{"pmid":"18413740","id":"PMC_18413740","title":"DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18413740","citation_count":39,"is_preprint":false},{"pmid":"26849232","id":"PMC_26849232","title":"Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is involved in cervical cancer stemness and can be a target of immunotherapy.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26849232","citation_count":39,"is_preprint":false},{"pmid":"18632606","id":"PMC_18632606","title":"CTCFL/BORIS is a methylation-independent DNA-binding protein that preferentially binds to the paternal H19 differentially methylated region.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18632606","citation_count":38,"is_preprint":false},{"pmid":"16741971","id":"PMC_16741971","title":"Antitumor efficacy of DNA vaccination to the epigenetically acting tumor promoting transcription factor BORIS and CD80 molecular adjuvant.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16741971","citation_count":37,"is_preprint":false},{"pmid":"28645561","id":"PMC_28645561","title":"BORIS up-regulates OCT4 via histone methylation to promote cancer stem cell-like properties in human liver cancer cells.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28645561","citation_count":36,"is_preprint":false},{"pmid":"17062669","id":"PMC_17062669","title":"The potential of BORIS detected in the leukocytes of breast cancer patients as an early marker of tumorigenesis.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/17062669","citation_count":36,"is_preprint":false},{"pmid":"22724006","id":"PMC_22724006","title":"A cell cycle role for the epigenetic factor CTCF-L/BORIS.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22724006","citation_count":33,"is_preprint":false},{"pmid":"30323717","id":"PMC_30323717","title":"BORIS: a key regulator of cancer stemness.","date":"2018","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/30323717","citation_count":30,"is_preprint":false},{"pmid":"24658009","id":"PMC_24658009","title":"Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24658009","citation_count":30,"is_preprint":false},{"pmid":"21641588","id":"PMC_21641588","title":"Cancer-testis antigen, BORIS based vaccine delivered by dendritic cells is extremely effective against a very aggressive and highly metastatic mouse mammary carcinoma.","date":"2011","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21641588","citation_count":30,"is_preprint":false},{"pmid":"24123052","id":"PMC_24123052","title":"Expression of the cancer-testis antigen BORIS correlates with prostate cancer.","date":"2013","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/24123052","citation_count":29,"is_preprint":false},{"pmid":"21659515","id":"PMC_21659515","title":"Transcription factor BORIS (Brother of the Regulator of Imprinted Sites) directly induces expression of a cancer-testis antigen, TSP50, through regulated binding of BORIS to the promoter.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21659515","citation_count":29,"is_preprint":false},{"pmid":"22792300","id":"PMC_22792300","title":"Dose-dependent activation of putative oncogene SBSN by BORIS.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22792300","citation_count":29,"is_preprint":false},{"pmid":"22168535","id":"PMC_22168535","title":"Expression of the epigenetic factor BORIS (CTCFL) in the human genome.","date":"2011","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22168535","citation_count":28,"is_preprint":false},{"pmid":"35940258","id":"PMC_35940258","title":"AMPKα2/HNF4A/BORIS/GLUT4 pathway promotes hepatocellular carcinoma cell invasion and metastasis in low glucose microenviroment.","date":"2022","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35940258","citation_count":28,"is_preprint":false},{"pmid":"28104398","id":"PMC_28104398","title":"Down-regulation of BORIS/CTCFL efficiently regulates cancer stemness and metastasis in MYCN amplified neuroblastoma cell line by modulating Wnt/β-catenin signaling pathway.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28104398","citation_count":28,"is_preprint":false},{"pmid":"27588042","id":"PMC_27588042","title":"The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements.","date":"2016","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/27588042","citation_count":28,"is_preprint":false},{"pmid":"23390377","id":"PMC_23390377","title":"BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer.","date":"2013","source":"Cancer immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23390377","citation_count":25,"is_preprint":false},{"pmid":"23019417","id":"PMC_23019417","title":"Apicidin and docetaxel combination treatment drives CTCFL expression and HMGB1 release acting as potential antitumor immune response inducers in metastatic breast cancer cells.","date":"2012","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23019417","citation_count":25,"is_preprint":false},{"pmid":"17972923","id":"PMC_17972923","title":"DNA, but not protein vaccine based on mutated BORIS antigen significantly inhibits tumor growth and prolongs the survival of mice.","date":"2007","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17972923","citation_count":25,"is_preprint":false},{"pmid":"25279549","id":"PMC_25279549","title":"High expression of hTERT and stemness genes in BORIS/CTCFL positive cells isolated from embryonic cancer cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25279549","citation_count":24,"is_preprint":false},{"pmid":"21325284","id":"PMC_21325284","title":"CTCF and BORIS regulate Rb2/p130 gene transcription: a novel mechanism and a new paradigm for understanding the biology of lung cancer.","date":"2011","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/21325284","citation_count":24,"is_preprint":false},{"pmid":"34158481","id":"PMC_34158481","title":"The combined action of CTCF and its testis-specific paralog BORIS is essential for spermatogenesis.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34158481","citation_count":23,"is_preprint":false},{"pmid":"28098226","id":"PMC_28098226","title":"Brother of Regulator of Imprinted Sites (BORIS) suppresses apoptosis in colorectal cancer.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28098226","citation_count":23,"is_preprint":false},{"pmid":"32123577","id":"PMC_32123577","title":"BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cells.","date":"2020","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/32123577","citation_count":21,"is_preprint":false},{"pmid":"21874228","id":"PMC_21874228","title":"Genome-wide copy number profiling using a 100K SNP array reveals novel disease-related genes BORIS and TSHZ1 in juvenile angiofibroma.","date":"2011","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21874228","citation_count":21,"is_preprint":false},{"pmid":"23237599","id":"PMC_23237599","title":"BORIS, brother of the regulator of imprinted sites, is aberrantly expressed in hepatocellular carcinoma.","date":"2012","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/23237599","citation_count":20,"is_preprint":false},{"pmid":"21811597","id":"PMC_21811597","title":"Widespread expression of BORIS/CTCFL in normal and cancer cells.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21811597","citation_count":19,"is_preprint":false},{"pmid":"31292201","id":"PMC_31292201","title":"BORIS Expression in Ovarian Cancer Precursor Cells Alters the CTCF Cistrome and Enhances Invasiveness through GALNT14.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/31292201","citation_count":19,"is_preprint":false},{"pmid":"20305816","id":"PMC_20305816","title":"BORIS (CTCFL) is not expressed in most human breast cell lines and high grade breast carcinomas.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20305816","citation_count":18,"is_preprint":false},{"pmid":"37026005","id":"PMC_37026005","title":"PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37026005","citation_count":17,"is_preprint":false},{"pmid":"29860503","id":"PMC_29860503","title":"Choice of binding sites for CTCFL compared to CTCF is driven by chromatin and by sequence preference.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29860503","citation_count":17,"is_preprint":false},{"pmid":"29077515","id":"PMC_29077515","title":"Discovering a binary CTCF code with a little help from BORIS.","date":"2017","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/29077515","citation_count":17,"is_preprint":false},{"pmid":"28248963","id":"PMC_28248963","title":"Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is a novel target of lung cancer stem-like cell immunotherapy.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28248963","citation_count":17,"is_preprint":false},{"pmid":"31406110","id":"PMC_31406110","title":"The epigenetic factor BORIS (CTCFL) controls the androgen receptor regulatory network in ovarian cancer.","date":"2019","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31406110","citation_count":16,"is_preprint":false},{"pmid":"23955684","id":"PMC_23955684","title":"Lack of association of MTHFR rs1801133 polymorphism and CTCFL mutations with sperm methylation errors in infertile patients.","date":"2013","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23955684","citation_count":16,"is_preprint":false},{"pmid":"28145452","id":"PMC_28145452","title":"Testis-specific transcriptional regulators selectively occupy BORIS-bound CTCF target regions in mouse male germ cells.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28145452","citation_count":15,"is_preprint":false},{"pmid":"30498011","id":"PMC_30498011","title":"MAGEA1 inhibits the expression of BORIS via increased promoter methylation.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30498011","citation_count":14,"is_preprint":false},{"pmid":"21034534","id":"PMC_21034534","title":"Susceptibility for breast cancer in young patients with short rare minisatellite alleles of BORIS.","date":"2010","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/21034534","citation_count":14,"is_preprint":false},{"pmid":"25363021","id":"PMC_25363021","title":"Differential regulation of MAGE-A1 promoter activity by BORIS and Sp1, both interacting with the TATA binding protein.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25363021","citation_count":13,"is_preprint":false},{"pmid":"22544282","id":"PMC_22544282","title":"Integrating role of T antigen, Rb2/p130, CTCF and BORIS in mediating non-canonical endoplasmic reticulum-dependent death pathways triggered by chronic ER stress in mouse medulloblastoma.","date":"2012","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22544282","citation_count":13,"is_preprint":false},{"pmid":"20438700","id":"PMC_20438700","title":"Molecular architecture of CTCFL.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20438700","citation_count":12,"is_preprint":false},{"pmid":"35918747","id":"PMC_35918747","title":"BTApep-TAT peptide inhibits ADP-ribosylation of BORIS to induce DNA damage in cancer.","date":"2022","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35918747","citation_count":12,"is_preprint":false},{"pmid":"24279897","id":"PMC_24279897","title":"BORIS/CTCFL is an RNA-binding protein that associates with polysomes.","date":"2013","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24279897","citation_count":11,"is_preprint":false},{"pmid":"30275357","id":"PMC_30275357","title":"Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies.","date":"2018","source":"High-throughput","url":"https://pubmed.ncbi.nlm.nih.gov/30275357","citation_count":11,"is_preprint":false},{"pmid":"22223638","id":"PMC_22223638","title":"Intronic promoter drives the BORIS-regulated expression of FerT in colon carcinoma cells.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22223638","citation_count":11,"is_preprint":false},{"pmid":"35182955","id":"PMC_35182955","title":"BORIS-mediated generation of circular RNAs induces inflammation.","date":"2022","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35182955","citation_count":10,"is_preprint":false},{"pmid":"38297316","id":"PMC_38297316","title":"BORIS/CTCFL epigenetically reprograms clustered CTCF binding sites into alternative transcriptional start sites.","date":"2024","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/38297316","citation_count":9,"is_preprint":false},{"pmid":"26169830","id":"PMC_26169830","title":"Expression of the CTCFL Gene during Mouse Embryogenesis Causes Growth Retardation, Postnatal Lethality, and Dysregulation of the Transforming Growth Factor β Pathway.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26169830","citation_count":9,"is_preprint":false},{"pmid":"36692143","id":"PMC_36692143","title":"Boris knockout eliminates AOM/DSS-induced in situ colorectal cancer by suppressing DNA damage repair and inflammation.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36692143","citation_count":9,"is_preprint":false},{"pmid":"32386482","id":"PMC_32386482","title":"Hypomethylation of CTCFL promoters as a noninvasive biomarker in plasma from patients with hepatocellular carcinoma.","date":"2020","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/32386482","citation_count":9,"is_preprint":false},{"pmid":"26125810","id":"PMC_26125810","title":"BORIS and CTCF are overexpressed in squamous intraepithelial lesions and cervical cancer.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26125810","citation_count":9,"is_preprint":false},{"pmid":"33227379","id":"PMC_33227379","title":"Symbiogenesis as a driving force of evolution: The legacy of Boris Kozo-Polyansky.","date":"2020","source":"Bio Systems","url":"https://pubmed.ncbi.nlm.nih.gov/33227379","citation_count":9,"is_preprint":false},{"pmid":"34534628","id":"PMC_34534628","title":"BORIS/CTCFL expression activates the TGFβ signaling cascade and induces Drp1 mediated mitochondrial fission in neuroblastoma.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34534628","citation_count":8,"is_preprint":false},{"pmid":"38810696","id":"PMC_38810696","title":"CTCF and BORIS-mediated autophagy regulation via alternative splicing of BNIP3L in breast cancer.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38810696","citation_count":8,"is_preprint":false},{"pmid":"34721660","id":"PMC_34721660","title":"Transcription Factor CTCFL Promotes Cell Proliferation, Migration, and Invasion in Gastric Cancer via Activating DPPA2.","date":"2021","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34721660","citation_count":7,"is_preprint":false},{"pmid":"35132075","id":"PMC_35132075","title":"CTCFL regulates the PI3K-Akt pathway and it is a target for personalized ovarian cancer therapy.","date":"2022","source":"NPJ systems biology and applications","url":"https://pubmed.ncbi.nlm.nih.gov/35132075","citation_count":7,"is_preprint":false},{"pmid":"29385718","id":"PMC_29385718","title":"The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis.","date":"2018","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29385718","citation_count":7,"is_preprint":false},{"pmid":"32884037","id":"PMC_32884037","title":"Early vertebrate origin of CTCFL, a CTCF paralog, revealed by proximity-guided shark genome scaffolding.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32884037","citation_count":7,"is_preprint":false},{"pmid":"30499053","id":"PMC_30499053","title":"Short rare minisatellite variant of BORIS-MS2 is related to bladder cancer susceptibility.","date":"2018","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/30499053","citation_count":6,"is_preprint":false},{"pmid":"24928684","id":"PMC_24928684","title":"Expression analysis of BORIS during pluripotent, differentiated, cancerous, and non-cancerous cell states.","date":"2014","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/24928684","citation_count":6,"is_preprint":false},{"pmid":"21495859","id":"PMC_21495859","title":"Analysis of promoter methylation and polymorphic minisatellites of BORIS and lack of association with gastric cancer.","date":"2011","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21495859","citation_count":6,"is_preprint":false},{"pmid":"28416107","id":"PMC_28416107","title":"Characteristics of the peritumoral pseudocapsule vary predictably with histologic subtype of T1 renal neoplasms. Jacob JM, Williamson SR, Gondim DD, Leese JA, Terry C, Grignon DJ, Boris RS.Urology. November 2015;86(5):956-961.","date":"2017","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28416107","citation_count":6,"is_preprint":false},{"pmid":"31949703","id":"PMC_31949703","title":"Atractyloside mimics BORIS knockdown to induce DNA damage in colorectal cancer cells.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31949703","citation_count":5,"is_preprint":false},{"pmid":"31934165","id":"PMC_31934165","title":"The expression of transcription factor BORIS and its association with the estrogen receptor beta (ER-β) in cervical carcinogenesis.","date":"2019","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31934165","citation_count":5,"is_preprint":false},{"pmid":"37082838","id":"PMC_37082838","title":"BORIS/CTCFL-mediated chromatin accessibility alterations promote a pro-invasive transcriptional signature in melanoma cells.","date":"2023","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/37082838","citation_count":4,"is_preprint":false},{"pmid":"19675668","id":"PMC_19675668","title":"No evidence for mutations of CTCFL/BORIS in Silver-Russell syndrome patients with IGF2/H19 imprinting control region 1 hypomethylation.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19675668","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49868,"output_tokens":9823,"usd":0.148475,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20419,"output_tokens":5709,"usd":0.12241,"stage2_stop_reason":"end_turn"},"total_usd":0.270885,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"CTCFL/BORIS is a paralog of CTCF sharing the same 11-zinc-finger DNA-binding domain (encoded by identical exons) but with distinct amino and carboxy termini; it is expressed exclusively in testis in a mutually exclusive pattern with CTCF during male germ cell development, coinciding with erasure of methylation marks during epigenetic reprogramming.\",\n      \"method\": \"Molecular cloning, sequence analysis, Northern/Western blot, expression profiling in testis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original cloning and characterization with multiple orthogonal methods; independently replicated across many subsequent studies\",\n      \"pmids\": [\"12011441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Overexpression of BORIS in normally BORIS-negative somatic cells promotes cell growth and can lead to transformation, whereas CTCF overexpression blocks cell proliferation, demonstrating antagonistic functional roles.\",\n      \"method\": \"Ectopic expression in somatic cell lines, cell proliferation assays\",\n      \"journal\": \"Seminars in cancer biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay, single lab, confirmed in subsequent studies\",\n      \"pmids\": [\"12191639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Conditional expression of BORIS in normal fibroblasts causes switching from CTCF to BORIS occupancy at an 11ZF target site in the MAGE-A1 promoter (a site insensitive to CpG methylation), leading to demethylation and transcriptional activation of MAGE-A1 and other cancer-testis genes; anti-BORIS shRNA prior to 5-azadC treatment blocked MAGE-A1 reactivation.\",\n      \"method\": \"Conditional BORIS expression, ChIP, bisulfite sequencing, shRNA knockdown, reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP, shRNA rescue, multiple orthogonal methods; replicated in parallel study (PMID:16140944)\",\n      \"pmids\": [\"16140943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BORIS binds a novel CTCF/BORIS-binding site in the NY-ESO-1 promoter (insensitive to CpG methylation in vitro); in vivo, CTCF occupancy correlates with NY-ESO-1 silencing while switching from CTCF to BORIS occupancy coincides with NY-ESO-1 derepression in lung cancer cells.\",\n      \"method\": \"Gel-shift assay, ChIP, bisulfite sequencing, methylation-specific PCR, co-transfection reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (EMSA, ChIP, reporter); replicated with complementary study (PMID:16140943)\",\n      \"pmids\": [\"16140944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CTCFL/BORIS interacts with PRMT7 (a protein arginine methyltransferase) and stimulates PRMT7's histone-methyltransferase activity via interactions with both histones and PRMT7; symmetrical dimethyl arginine 3 of histone H4 (catalyzed by PRMT7) accumulates in germ cells during ICR methylation. Nuclear co-injection of CTCFL, PRMT7, Dnmt3a, Dnmt3b, and DnmtL expression vectors in Xenopus oocytes was sufficient to drive H19 ICR methylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro histone methyltransferase assay, ChIP, Xenopus oocyte co-injection\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with reconstitution in Xenopus oocytes, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17048991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BORIS expression is regulated by three alternative promoters (A, B, C) that are negatively regulated by DNA methylation and by functional p53; reduction of CTCF in normally BORIS-negative fibroblasts leads to derepression of BORIS promoters, establishing CTCF as a transcriptional repressor of BORIS.\",\n      \"method\": \"5' RACE, promoter-reporter assays, bisulfite sequencing, CTCF knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter dissection with multiple methods, single lab\",\n      \"pmids\": [\"17962299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BORIS physically interacts with Sp1 (but not with CTCF) in vivo, and BORIS recruits Sp1 to the proximal Sp1-binding site of the NY-ESO-1 promoter to mediate its derepression in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, gel-shift assay, siRNA knockdown, promoter-reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus ChIP, single lab\",\n      \"pmids\": [\"17260018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CTCFL/BORIS is a methylation-independent DNA-binding protein; ChIP and EMSA using whole-cell extracts and in vitro translated protein showed BORIS binds methylated DNA while CTCF preferentially binds unmethylated DNA. In murine hybrid cells, BORIS preferentially binds the methylated paternal H19 differentially methylated region.\",\n      \"method\": \"ChIP, EMSA with in vitro translated protein, methylation-specific ChIP-PCR, murine hybrid cell system\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro translated protein EMSA plus allele-specific ChIP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"18632606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA methyltransferases DNMT1 and DNMT3B activate BAG-1 expression by recruiting CTCFL/BORIS to the BAG-1 promoter, which is associated with a permissive dimethyl-H3K4/dimethyl-H3K9 chromatin state; BORIS shRNA knockdown decreased BORIS promoter binding and BAG-1 expression and shifted the chromatin to a non-permissive state.\",\n      \"method\": \"ChIP, shRNA knockdown, DNMT-overexpressing and knockout cell lines\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with shRNA functional validation, single lab\",\n      \"pmids\": [\"18413740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BORIS binds to and activates the testis-specific CST (Gal3st1 form F_TS) promoter; mutation of the BORIS binding site in the promoter abrogated BORIS binding and activation. BORIS knockout mice showed reduced CST expression, delayed haploid cell production, and increased germ cell death.\",\n      \"method\": \"BORIS knockout mice, gene expression profiling, ChIP, promoter-reporter assay with binding site mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO mouse phenotype combined with ChIP and mutagenesis-based promoter assay\",\n      \"pmids\": [\"20231363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Exogenous BORIS expression in normal BORIS-negative cells is sufficient to activate hTERT transcription; both CTCF and BORIS bind the first exon of hTERT in vivo in cancer cells, and BORIS counteracts the inhibitory effect of CTCF on hTERT.\",\n      \"method\": \"Ectopic BORIS expression, ChIP, quantitative RT-PCR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional overexpression, single lab\",\n      \"pmids\": [\"20876690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BORIS is expressed as 23 isoforms with alternative N- and C-termini and varying zinc finger numbers; all isoforms are translated and localize to the nucleus. Binding to DNA targets is methylation-sensitive and depends on the number and composition of zinc fingers; a specific long N-terminus (N258) combined with DNA-binding ability is necessary and sufficient for transcriptional activation of CST.\",\n      \"method\": \"RT-PCR isoform characterization, western blot, nuclear localization assay, EMSA, reporter assays with isoform-specific constructs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple isoforms characterized with functional assays, single lab\",\n      \"pmids\": [\"21079786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BORIS directly binds two conserved binding sites in the TSP50 promoter in a methylation-independent but nucleosome-occupancy-dependent manner and activates TSP50 transcription; mutation of binding sites abolished BORIS binding and promoter activation.\",\n      \"method\": \"ChIP, EMSA, promoter-reporter assay with binding site mutagenesis, DNase I sensitivity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding with mutagenesis plus ChIP and reporter assays, multiple orthogonal methods\",\n      \"pmids\": [\"21659515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BORIS binds to the promoters of MAGEA2, MAGEA3, and MAGEA4 and activates their expression by inducing a shift to open chromatin; MAGEA3 activation involved promoter demethylation while MAGEA2 and MAGEA4 activation was independent of promoter demethylation.\",\n      \"method\": \"Doxycycline-inducible BORIS expression, ChIP, luciferase reporter assay, bisulfite sequencing, siRNA knockdown\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with ChIP and bisulfite sequencing, single lab\",\n      \"pmids\": [\"21558405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BORIS binds to the intronic ferT promoter and is required for FerT expression in colorectal cancer cells; BORIS knockdown significantly decreases ferT expression and correlates with hypomethylation of the ferT promoter.\",\n      \"method\": \"ChIP, siRNA knockdown, bisulfite sequencing, RT-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional knockdown, single lab\",\n      \"pmids\": [\"22223638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CTCFL is expressed only transiently in spermatogonia and preleptotene spermatocytes, colocalizing with CTCF; absence of CTCFL causes subfertility with partially penetrant testicular atrophy and reduced expression of testis-specific genes (Gal3st1, Prss50). CTCFL binds promoters with loosely assembled nucleosomes whereas CTCF favors sites with phased nucleosomes. An ES cell rescue assay shows CTCFL is functionally distinct from CTCF.\",\n      \"method\": \"Immunohistochemistry, live-cell fluorescence microscopy, CTCFL KO mice, genome-wide RNA expression, genome-wide ChIP-seq, ES cell rescue assay\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO mouse plus genome-wide binding analysis plus functional rescue assay with multiple orthogonal methods\",\n      \"pmids\": [\"22709888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BORIS localizes to the nucleolus (within nucleolin core structure, adjacent to fibrillarin) and to interphase centrosomes in keratinocytes; endogenous BORIS is present at active transcription sites. Blocking cell cycle at S phase or causing DNA damage produces striking BORIS accumulation. Ectopic BORIS expression increases S-phase cells and causes genomic instability; BORIS shRNA inhibits RNA transcription and cell cycle progression.\",\n      \"method\": \"Immunofluorescence, nascent RNA labeling, live-cell GFP imaging, cell cycle analysis, shRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with live imaging plus functional KD phenotype, single lab\",\n      \"pmids\": [\"22724006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dose-dependent BORIS expression induces SBSN activation at low concentrations via CpG island demethylation and chromatin opening at the SBSN TSS, while higher BORIS concentrations suppress SBSN via chromatin repression; increasing BORIS also reduces cell growth and colony formation in a dose-dependent manner.\",\n      \"method\": \"Doxycycline-inducible BORIS expression, bisulfite sequencing, ChIP, RT-PCR, colony formation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible dose-response system with ChIP and bisulfite sequencing, single lab\",\n      \"pmids\": [\"22792300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Both BORIS and CTCF cause significant decrease in cell proliferation and clonogenic capacity and suppress breast cancer growth in an orthotopic model in vivo; both confer protective effects during UV-induced apoptosis in primary cells, challenging the simple oncogenic model for BORIS.\",\n      \"method\": \"Inducible lentiviral expression, cell proliferation assay, clonogenic assay, bioluminescent orthotopic mouse model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro plus in vivo functional assays, single lab\",\n      \"pmids\": [\"23553099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BORIS/CTCFL is an RNA-binding protein; it associates with mRNA in neural stem cells and neurons, and co-fractionates with actively translating polysomes. The majority of BORIS-associated transcripts differ between cell types. BORIS contains a putative nuclear export signal in the C-terminal domain.\",\n      \"method\": \"RNA immunoprecipitation, polysome profiling, domain analysis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP plus polysome profiling, single lab\",\n      \"pmids\": [\"24279897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BORIS and Sp1 have opposing effects on MAGE-A1 promoter activity; both BORIS and Sp1 interact with the TATA-binding protein (hTBP), suggesting competitive regulation. Sp1 partially represses BORIS-mediated stimulation of the MAGE-A1 promoter. Ectopic BORIS also activates transcription from its own locus, inducing all splice variants.\",\n      \"method\": \"Luciferase reporter assays, ChIP, GST pull-down, quantitative RT-PCR, bisulfite sequencing\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down plus reporter assays with ChIP, single lab\",\n      \"pmids\": [\"25363021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTCFL and CTCF co-occupy a specific subset of regulatory elements with clustered CTCF binding motifs (2xCTSes); 2xCTSes are preferentially found at active promoters and enhancers in cancer and germ cells. BORIS depletion in K562 cells alters transcription of many genes and induces differentiation; ectopic BORIS in MCF7 cells induces specific transcriptional changes.\",\n      \"method\": \"Genome-wide ChIP-seq, BORIS depletion (siRNA/shRNA), ectopic expression, gene expression profiling\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with functional loss- and gain-of-function experiments, independently expanded in subsequent studies\",\n      \"pmids\": [\"26268681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BORIS binds preferentially to the VNTR region of SVA transposable elements in vivo (distinct from CTCF binding to the CTCF motif); RNA-seq shows BORIS largely represses SVA expression alongside DNA and histone methylation, with exception of promoter capture by SVA.\",\n      \"method\": \"ChIP-chip, ChIP-seq, RNA-seq\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq plus RNA-seq, single lab\",\n      \"pmids\": [\"27588042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Intragenic DNA methylation at the PKM alternative exon enables BORIS binding, which promotes cancer-specific PKM2 splicing and the Warburg effect; BORIS depletion or deletion of the BORIS binding site by CRISPR/Cas9 switches splicing from PKM2 to PKM1, reversing the Warburg effect and inhibiting breast cancer cell growth. BORIS also regulates alternative splicing of several other genes in a DNA methylation-dependent manner.\",\n      \"method\": \"BORIS depletion (siRNA), CRISPR/Cas9 binding site deletion, RT-PCR for splicing isoforms, metabolic assays, cell growth assays, bisulfite sequencing\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR deletion plus siRNA knockdown plus metabolic readout, multiple orthogonal methods\",\n      \"pmids\": [\"29073069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BORIS binds near the TGFB1 promoter, coinciding with increased TGFB1 expression, and promotes a switch from a proliferative to an invasive phenotype in melanoma cells; inducible BORIS overexpression reduces proliferation and increases migration and invasion.\",\n      \"method\": \"Inducible BORIS overexpression, whole-transcriptome analysis (RNA-seq), ChIP, migration/invasion assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional assays with transcriptome analysis, single lab\",\n      \"pmids\": [\"32123577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BORIS up-regulates OCT4 via histone methylation: BORIS binding at the OCT4 promoter increases H3K4me2 and reduces H3K27me3, without affecting DNA methylation at the OCT4 promoter. BORIS overexpression promotes cancer stem cell-like properties in liver cancer cells.\",\n      \"method\": \"ChIP, bisulfite sequencing, BORIS overexpression and knockdown, sphere formation and tumor-initiating assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for histone marks plus functional assays, single lab\",\n      \"pmids\": [\"28645561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BORIS activates the TGFB1 pathway in neuroblastoma; BORIS stabilizes SMAD3 and SMAD4 transcripts, and loss of BORIS abrogates both canonical and non-canonical TGFβ signaling. Ectopic BORIS expression also induces Drp1 phosphorylation (Ser616), promoting mitochondrial fission and a metabolic switch toward glycolysis.\",\n      \"method\": \"BORIS overexpression and knockdown, RT-PCR, western blot (pathway components), oxygen consumption rate measurement\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain- and loss-of-function with pathway readouts, single lab\",\n      \"pmids\": [\"34534628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTCFL binding site selection versus CTCF is driven by chromatin state: CTCFL is enriched at open chromatin marked by H3K27ac, H3K4me2/3, H3K79me2, H3K9ac, and H2A.Z, particularly at TSS regions. Specific nucleotide positions in the binding motif are critical for CTCFL but not CTCF binding.\",\n      \"method\": \"ChIP-seq, ATAC-seq, motif analysis, genome-wide binding comparison\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with chromatin state correlations, single lab\",\n      \"pmids\": [\"29860503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BORIS promotes chromatin looping interactions in ALK-inhibitor-resistant, MYCN-amplified neuroblastoma cells; resistance is accompanied by loss of MYCN expression followed by BORIS overexpression. BORIS-regulated alterations in chromatin looping form super-enhancers that drive ectopic expression of proneural transcription factors defining the resistance phenotype.\",\n      \"method\": \"Hi-C/chromatin conformation capture, ChIP-seq, BORIS overexpression and depletion, RNA-seq, resistance model development\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide chromatin conformation plus ChIP-seq plus functional rescue in a rigorous resistance model\",\n      \"pmids\": [\"31391581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BORIS expression in fallopian tube secretory epithelial cells (FTSEC) increases motility and invasion, and induces GALNT14 (a glycosyltransferase implicated in cancer cell migration); GALNT14 knockdown significantly abrogates BORIS-induced motility and invasion. BORIS expression is also associated with de novo and enhanced CTCF binding at hundreds of loci correlated with transcriptional activation.\",\n      \"method\": \"Lentiviral BORIS expression in FTSEC, migration/invasion assays, siRNA knockdown of GALNT14, RNA-seq, ChIP-seq\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis (GALNT14 KD rescue) plus ChIP-seq, single lab\",\n      \"pmids\": [\"31292201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGEA1 interacts with CTCF to form a protein complex with DNMT3a; this complex binds the BORIS promoter, recruits DNMT3a, and causes hypermethylation and repression of BORIS expression. The MAGEA1-CTCF interaction is required for DNMT3a recruitment.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, co-localization assay, ChIP, bisulfite sequencing, siRNA knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and GST pull-down plus ChIP and bisulfite sequencing, single lab\",\n      \"pmids\": [\"30498011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The N-terminus of CTCF (not shared by CTCFL) interacts with cohesin, explaining why convergent CTCF binding sites are required for loop formation; CTCFL lacks this N-terminal cohesin interaction and therefore cannot mediate the same chromatin loops as CTCF. CTCF and CTCFL have phenotypically distinct binding sites; N, C, and zinc finger domains each play unique roles in targeting each paralog to distinct sites.\",\n      \"method\": \"Inducible complementation system expressing CTCFL and CTCF-CTCFL chimeras ± endogenous CTCF, ChIP-seq, Hi-C, RNA-seq\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain-swap chimera approach with genome-wide Hi-C and ChIP-seq in presence/absence of CTCF\",\n      \"pmids\": [\"32393311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BORIS heterodimerizes with CTCF and combined depletion of both CTCF and BORIS (Ctcf+/-Boris-/- compound mutant mice) causes male sterility with reduced testes size, defective meiotic recombination, increased apoptosis, and malformed spermatozoa; chromatin binding of CTCF is preferentially lost from CTCF-BORIS heterodimeric sites. Combined action is required to repress pre-meiotic genes and activate post-meiotic spermatogenesis genes.\",\n      \"method\": \"Mouse genetic models (compound mutants with varied CTCF/BORIS levels), ChIP-seq, RNA-seq, fertility assays, histology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — rigorous genetic epistasis with compound mutant mice plus genome-wide ChIP-seq and RNA-seq\",\n      \"pmids\": [\"34158481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTCFL expression during mouse embryogenesis dysregulates the TGFβ pathway; transcriptome sequencing of Ctcfl-expressing ES cells revealed 14 deregulated genes with TGFβ pathway as most affected, and Ctcfl-expressing embryos show growth retardation, eye malformations, vascular defects, and neonatal death.\",\n      \"method\": \"Tetracycline-inducible transgenic mice, ES cell-tetraploid chimeras, RNA-seq, bioinformatic pathway analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible transgenic mouse model with transcriptome sequencing, single lab\",\n      \"pmids\": [\"26169830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BORIS undergoes ADP ribosylation at five conserved glutamic acid residues (E198–E228) upon DNA double- or single-strand damage; this modification is required for BORIS interaction with Ku70 and for BORIS function in DNA damage repair. Inhibiting ADP ribosylation (by site-specific mutation or by BTApep-TAT peptide) blocks BORIS-Ku70 interaction and impairs DNA damage repair.\",\n      \"method\": \"Phage display peptide inhibitor (BTApep-TAT), site-directed mutagenesis, co-immunoprecipitation, γH2AX assay, RNA-seq, xenograft mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of PTM sites plus co-IP functional validation plus in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"35918747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HNF4A directly binds the BORIS promoter and negatively regulates BORIS expression; BORIS in turn directly binds the GLUT4 promoter and positively regulates GLUT4 expression, promoting hepatoma cell motility and metastasis in low-glucose conditions (AMPKα2/HNF4A/BORIS/GLUT4 pathway).\",\n      \"method\": \"ChIP, overexpression and knockdown complementation experiments, bioinformatic analysis, invasion/metastasis assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional epistasis experiments, single lab\",\n      \"pmids\": [\"35940258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BORIS/CTCFL epigenetically reprograms intergenic and intronic CTCF binding sites (2xCTSes) into active de novo promoters by recruiting the chromatin remodeling factor SRCAP, causing replacement of H2A with H2A.Z and relaxation of flanking nucleosomes; this facilitates recruitment of additional transcription factors and activates cancer-testis gene expression, lncRNAs, retro-pseudogenes, and dormant transposable elements.\",\n      \"method\": \"ChIP-seq, ATAC-seq, RNA-seq, co-immunoprecipitation (BORIS-SRCAP interaction), H2A.Z ChIP, BORIS depletion and overexpression\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic reconstitution with co-IP of SRCAP, genome-wide chromatin remodeling assays, multiple orthogonal methods\",\n      \"pmids\": [\"38297316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BORIS binds methylated BNIP3L intron 1 under normoxia (while CTCF binds unmethylated intron 1 under hypoxia); BORIS binding causes RNA Pol-II pausing and recruits SRSF6, redirecting proximal splice-site selection to exclude exon 1 from BNIP3L mRNA (generating BNIP3L-Δ1 isoform), thereby inhibiting autophagy.\",\n      \"method\": \"ChIP (CTCF, BORIS, RNA Pol-II), bisulfite sequencing, RT-PCR splicing assay, siRNA knockdown, SRSF6 interaction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with bisulfite sequencing and functional splicing assays, single lab\",\n      \"pmids\": [\"38810696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BORIS physically interacts with TBP-associated factor 7-like (TAF7L) in germ cells; BORIS-bound 2xCTS regions are co-occupied by multiple testis-specific transcriptional regulators and are associated with highly expressed germ cell-specific genes and histone retention in mature spermatozoa.\",\n      \"method\": \"Co-immunoprecipitation (BORIS-TAF7L), ChIP-seq in mouse germ cells, histone retention analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genome-wide ChIP-seq, single lab\",\n      \"pmids\": [\"28145452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA damage-induced upregulation of miR-709 in mouse testis (via ATR/Rfx1 signaling) targets BORIS mRNA and decreases BORIS protein levels, acting as a protective mechanism to prevent aberrant erasure of DNA methylation after radiation exposure.\",\n      \"method\": \"MicroRNA microarray, quantitative RT-PCR, miR-709 target validation (BORIS 3'UTR targeting)\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression-based target assignment with limited functional validation of BORIS as direct miR-709 target, single lab\",\n      \"pmids\": [\"19029807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The C-terminal fragment of CTCFL predominantly consists of extended and disordered content by biophysical analysis; computational analysis predicts the N-terminal segment is also disordered, suggesting that sequence divergence in the unstructured terminal segments drives differential cofactor recruitment to distinguish CTCFL from CTCF.\",\n      \"method\": \"Biophysical characterization of recombinant C-terminal fragment (secondary structure analysis), computational disorder prediction\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — partial structural characterization without functional mutagenesis validation, single lab\",\n      \"pmids\": [\"20438700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rb2/p130 forms complexes with CTCF or BORIS under ER stress conditions in mouse medulloblastoma cells; T antigen induces chronic ER stress, associated with Caspase-12 activation and formation of Rb2/p130-CTCF or Rb2/p130-BORIS complexes as part of a non-canonical ER-dependent death pathway.\",\n      \"method\": \"Co-immunoprecipitation, western blot, cell death assays in T-Ag positive/negative medulloblastoma cell lines\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP study with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"22544282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Boris knockout in mice reduces incidence and severity of AOM/DSS-induced colorectal cancer; Boris KO promotes γH2AX phosphorylation and DNA damage in colorectal cancer tissues, and suppresses Wnt and MAPK signaling (which mediate DNA damage repair callback). Boris KO also alleviates DSS-induced colitis via inhibition of NF-κB signaling in macrophages.\",\n      \"method\": \"Boris knockout mice, AOM/DSS colorectal cancer model, γH2AX immunofluorescence, western blot (Wnt, MAPK, NF-κB pathway), DSS-colitis model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO mouse cancer model with pathway analysis, single lab\",\n      \"pmids\": [\"36692143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTCFL/BORIS is a testis-specific paralog of CTCF sharing an identical 11-zinc-finger DNA-binding domain but with divergent N- and C-termini; it preferentially binds clustered CTCF target sites (2xCTSes) in a nucleosome-composition-dependent, largely methylation-independent manner, heterodimerizes with CTCF to cooperatively regulate spermatogenesis gene programs, and in cancer cells acts as a chromatin remodeler that recruits SRCAP to replace H2A with H2A.Z at CTCF sites, epigenetically converting them into active alternative promoters, while also regulating alternative splicing via DNA methylation-dependent binding at intragenic sites, interacting with PRMT7 to stimulate histone arginine methylation, associating with polysomes as an RNA-binding protein, and undergoing ADP ribosylation upon DNA damage to engage Ku70 in DNA damage repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTCFL (BORIS) is a testis-restricted paralog of CTCF that shares an identical 11-zinc-finger DNA-binding domain encoded by the same exons but carries divergent N- and C-termini, and it is expressed in a mutually exclusive pattern with CTCF during male germ-cell epigenetic reprogramming [#0]. Its terminal segments are intrinsically disordered, providing a structural basis for paralog-specific cofactor recruitment that distinguishes it from CTCF [#40]. CTCFL and CTCF co-occupy a subset of clustered CTCF target sites (2xCTSes) found at active promoters and enhancers, and the two proteins act combinatorially to repress pre-meiotic genes and activate post-meiotic spermatogenesis programs; combined depletion in mice causes male sterility, defective meiotic recombination, and germ-cell death [#21, #32]. Site selection by CTCFL is governed by chromatin state rather than methylation: it is targeted to open chromatin marked by H3K27ac, H3K4me2/3 and H2A.Z and to loosely assembled nucleosomes, and unlike CTCF it lacks the N-terminal cohesin-interaction module required for canonical loop formation [#15, #27, #31]. Mechanistically, CTCFL functions as a chromatin remodeler that recruits the SRCAP complex to exchange H2A for H2A.Z and relax flanking nucleosomes, converting intergenic and intronic CTCF sites into active de novo promoters that drive cancer-testis genes, lncRNAs, and dormant transposable elements [#36]. It also stimulates PRMT7-catalyzed symmetric H4R3 dimethylation during germ-cell imprint establishment [#4], and in cancer cells it reactivates silenced loci such as MAGE-A1 and NY-ESO-1 through a CTCF-to-BORIS occupancy switch and chromatin opening [#2, #3, #13]. Beyond transcription, CTCFL binds intragenic methylated DNA to control alternative splicing—promoting cancer-specific PKM2 splicing and the Warburg effect—is an RNA-binding protein that co-fractionates with translating polysomes, and undergoes DNA-damage-induced ADP-ribosylation that recruits Ku70 for DNA damage repair [#23, #19, #34]. In neuroblastoma it remodels chromatin looping to generate super-enhancers driving drug resistance [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that CTCFL is a distinct, testis-specific CTCF paralog rather than a redundant copy, defining the central puzzle of two proteins sharing a DNA-binding domain but separated in space and time.\",\n      \"evidence\": \"Molecular cloning, sequence analysis, and testis expression profiling against CTCF\",\n      \"pmids\": [\"12011441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define genome-wide binding differences from CTCF\", \"Mechanism of mutually exclusive expression not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"First evidence that CTCFL and CTCF have antagonistic effects on proliferation, framing CTCFL as a potential growth-promoting/transforming factor.\",\n      \"evidence\": \"Ectopic expression in somatic cell lines with proliferation assays\",\n      \"pmids\": [\"12191639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for growth promotion\", \"Later work (#18) challenged the simple oncogenic model\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that a CTCF-to-BORIS occupancy switch at methylation-insensitive 11ZF sites reactivates silenced cancer-testis genes (MAGE-A1, NY-ESO-1), linking paralog switching to epigenetic derepression.\",\n      \"evidence\": \"Conditional BORIS expression, reciprocal ChIP, bisulfite sequencing, shRNA rescue in fibroblasts and lung cancer cells\",\n      \"pmids\": [\"16140943\", \"16140944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin remodeling machinery recruited by BORIS not yet identified\", \"Generality across the genome untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified PRMT7 as a CTCFL cofactor, providing a histone-modification mechanism (symmetric H4R3 dimethylation) linking CTCFL to germline imprint establishment.\",\n      \"evidence\": \"Co-IP, in vitro histone methyltransferase assay, and Xenopus oocyte reconstitution of H19 ICR methylation\",\n      \"pmids\": [\"17048991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous requirement for CTCFL-PRMT7 in mammalian imprinting not shown\", \"Direct genomic targets of the complex undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined how BORIS is itself controlled, showing alternative promoters repressed by DNA methylation, p53, and CTCF, and identifying Sp1 as a recruited transcriptional partner at target promoters.\",\n      \"evidence\": \"5' RACE, promoter-reporter assays, CTCF knockdown, co-IP and ChIP for Sp1\",\n      \"pmids\": [\"17962299\", \"17260018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab promoter dissection\", \"Sp1 interaction not tested genome-wide\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the methylation question by showing BORIS binds methylated DNA (including the methylated paternal H19 DMR) while CTCF prefers unmethylated DNA, distinguishing the paralogs biochemically.\",\n      \"evidence\": \"EMSA with in vitro translated protein, methylation-specific and allele-specific ChIP in murine hybrid cells\",\n      \"pmids\": [\"18632606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with methylation-insensitive sites (#2,#3) left open\", \"Structural basis of methylated-DNA preference unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked BORIS to a germline gene program in vivo, showing it activates testis-specific genes and that its loss causes subfertility and germ-cell death.\",\n      \"evidence\": \"BORIS knockout mice, expression profiling, ChIP, and promoter mutagenesis for Gal3st1/CST\",\n      \"pmids\": [\"20231363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partial penetrance suggested redundancy not yet explained\", \"Cofactors driving activation in vivo not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated functional diversity of BORIS through 23 nuclear isoforms with variable zinc-finger composition, showing N-terminal identity and DNA binding jointly determine transcriptional activation.\",\n      \"evidence\": \"RT-PCR isoform characterization, EMSA, and isoform-specific reporter assays\",\n      \"pmids\": [\"21079786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological roles of individual isoforms unresolved\", \"Single-lab characterization\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established chromatin-state, not methylation alone, as the determinant of CTCFL versus CTCF targeting, with CTCFL favoring loosely assembled nucleosomes and being functionally non-interchangeable with CTCF.\",\n      \"evidence\": \"CTCFL KO mice, genome-wide ChIP-seq, and ES-cell rescue assay\",\n      \"pmids\": [\"22709888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Remodeler responsible for the loose-nucleosome state not yet identified\", \"Mechanism of distinct site targeting incompletely defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected BORIS to cell-cycle progression, transcription, and genomic instability, and localized it to nucleolus and centrosomes with accumulation upon S-phase arrest and DNA damage.\",\n      \"evidence\": \"Immunofluorescence, nascent RNA labeling, live-cell imaging, and shRNA knockdown in keratinocytes\",\n      \"pmids\": [\"22724006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Centrosomal/nucleolar functions not mechanistically dissected\", \"Link between DNA damage accumulation and repair not established here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the genomic logic of paralog co-occupancy: CTCFL and CTCF share clustered 2xCTSes enriched at active promoters/enhancers, and BORIS perturbation reprograms transcription and differentiation.\",\n      \"evidence\": \"Genome-wide ChIP-seq with loss- and gain-of-function in K562 and MCF7 cells\",\n      \"pmids\": [\"26268681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism converting 2xCTSes to active promoters not yet defined\", \"Cofactor recruitment at 2xCTSes unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended BORIS function to co-transcriptional RNA processing, showing intragenic methylation-dependent binding controls cancer-specific PKM2 splicing and the Warburg effect.\",\n      \"evidence\": \"siRNA depletion, CRISPR/Cas9 binding-site deletion, splicing RT-PCR, and metabolic assays in breast cancer cells\",\n      \"pmids\": [\"29073069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Splicing machinery recruited by BORIS not identified here\", \"Breadth of methylation-dependent splicing targets only partly mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified TAF7L as a germ-cell-specific BORIS partner and placed BORIS-bound 2xCTSes at highly expressed germ-cell genes with histone retention in spermatozoa.\",\n      \"evidence\": \"Co-IP and ChIP-seq in mouse germ cells with histone-retention analysis\",\n      \"pmids\": [\"28145452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TAF7L interaction untested\", \"Single-lab co-IP\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that BORIS reshapes 3D chromatin to form super-enhancers, driving an ALK-inhibitor-resistance transcriptional program in MYCN-amplified neuroblastoma.\",\n      \"evidence\": \"Hi-C, ChIP-seq, RNA-seq, and overexpression/depletion in a resistance model\",\n      \"pmids\": [\"31391581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which BORIS nucleates new loops without cohesin module unclear\", \"Whether looping is direct or downstream of transcription not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pinpointed the molecular reason CTCFL cannot replace CTCF in loop formation: the CTCF N-terminus binds cohesin while CTCFL lacks it, with each domain contributing to paralog-specific targeting.\",\n      \"evidence\": \"Inducible complementation with CTCF-CTCFL chimeras, ChIP-seq, and Hi-C ± endogenous CTCF\",\n      \"pmids\": [\"32393311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CTCFL still promotes looping in some contexts (#28) not reconciled\", \"Cofactors bound by the divergent CTCFL termini not fully enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed CTCF and BORIS heterodimerize and act combinatorially to control the meiotic-to-postmeiotic gene switch, with loss of both causing sterility and CTCF binding lost preferentially from heterodimeric sites.\",\n      \"evidence\": \"Compound mutant mice with graded CTCF/BORIS levels, ChIP-seq, RNA-seq, fertility and histology\",\n      \"pmids\": [\"34158481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of heterodimerization not defined\", \"Direct versus indirect target effects not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a non-transcriptional role in genome maintenance: DNA-damage-induced ADP-ribosylation of conserved glutamates licenses BORIS-Ku70 interaction and DNA repair.\",\n      \"evidence\": \"Site-directed mutagenesis, peptide inhibitor (BTApep-TAT), co-IP, γH2AX assay, and xenograft model\",\n      \"pmids\": [\"35918747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ADP-ribosyltransferase not established\", \"Repair pathway placement (NHEJ vs other) only inferred via Ku70\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Delivered the unifying chromatin-remodeling mechanism: BORIS recruits SRCAP to deposit H2A.Z and relax nucleosomes, converting silent CTCF sites into active de novo promoters for cancer-testis genes and repeats.\",\n      \"evidence\": \"ChIP-seq, ATAC-seq, H2A.Z ChIP, RNA-seq, and BORIS-SRCAP co-IP with depletion/overexpression\",\n      \"pmids\": [\"38297316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRCAP recruitment explains all BORIS-activated loci untested\", \"Connection to the disordered termini (#40) not directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CTCFL integrates its multiple activities—chromatin remodeling, methylation-dependent splicing, RNA binding, and DNA-damage repair—into a single coherent cellular program, and how its divergent disordered termini route it among these functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking disordered termini to specific cofactor choices\", \"Relative contribution of each activity to germ-cell versus cancer phenotypes unclear\", \"No reconstitution of full SRCAP-dependent promoter conversion in vitro\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7, 12, 21, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 9, 12, 21, 36]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [21, 36, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 21, 36]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [23, 37, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 9, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTCF\", \"PRMT7\", \"SRCAP\", \"Ku70\", \"Sp1\", \"TAF7L\", \"SRSF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}