{"gene":"HCFC1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2003,"finding":"Separate regions of HCF-1 critical for cell proliferation associate with the Sin3 histone deacetylase (HDAC) complex and a human trithorax-related Set1/Ash2 histone H3-K4 methyltransferase (HMT) complex; HCF-1 tethers these two complexes together, and the transcriptional activator VP16 selectively binds HCF-1 associated with the Set1/Ash2 HMT complex in the absence of the Sin3 HDAC complex.","method":"Co-immunoprecipitation, mass spectrometry, in vitro binding assays, domain mapping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain mapping, multiple orthogonal methods, widely replicated","pmids":["12670868"],"is_preprint":false},{"year":2001,"finding":"HCF-1 is naturally bound to chromatin in uninfected cells through its VP16 interaction domain (Kelch/beta-propeller domain); dissociation from chromatin in tsBN67 cells precedes and causes temperature-induced cell proliferation arrest.","method":"Chromatin fractionation, temperature-shift experiments, tsBN67 cell proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, direct fractionation with functional correlation, replicated across studies","pmids":["11340173"],"is_preprint":false},{"year":2011,"finding":"O-GlcNAc transferase (OGT) both O-GlcNAcylates the HCF-1N subunit and directly cleaves HCF-1 at the HCF-1PRO repeat sequences, performing site-specific proteolytic maturation; replacement of HCF-1PRO repeats with a heterologous cleavage signal promotes proteolysis but fails to activate HCF-1C M-phase functions, showing that OGT-mediated cleavage is specifically required for HCF-1C function.","method":"In vitro OGT cleavage assays, mutagenesis of HCF-1PRO repeats, cell-based M-phase progression assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with in vitro cleavage, mutagenesis, and functional cell-based validation in one rigorous study","pmids":["21295698"],"is_preprint":false},{"year":2013,"finding":"The tetratricopeptide-repeat (TPR) domain of OGT binds the C-terminal portion of an HCF-1 proteolytic repeat, positioning the cleavage region in the glycosyltransferase active site above UDP-GlcNAc; cleavage occurs between cysteine and glutamate residues producing a pyroglutamate product; mutation of the cleavage-site glutamate to serine converts an HCF-1 proteolytic repeat into a glycosylation substrate.","method":"Crystal structure of OGT:HCF-1PRO-repeat complex, active-site mutagenesis, biochemical cleavage assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus active-site mutagenesis plus in vitro biochemical validation","pmids":["24311690"],"is_preprint":false},{"year":2003,"finding":"HCF-1 regulates two distinct stages of the cell cycle via its two proteolytically generated subunits: HCF-1N promotes G1-phase progression, while HCF-1C ensures proper cytokinesis/exit from mitosis; siRNA depletion of HCF-1 in diverse mammalian cells caused both G1 arrest and cytokinesis defects, and proteolytic processing is required to separate and ensure these functions.","method":"siRNA knockdown in multiple mammalian cell lines, cell-cycle analysis, cytokinesis assays, expression of separated subunits","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function across multiple cell types with defined phenotypic readouts, replicated in multiple studies","pmids":["12743030"],"is_preprint":false},{"year":2004,"finding":"Depletion of the HCF-1C subunit causes mitotic defects including a switch from monomethyl to dimethyl H4-K20 and defective chromosome alignment/segregation; HCF-1C regulates expression of the H4-K20 methyltransferase PR-Set7, and upregulation of PR-Set7 upon HCF-1 loss leads to improper mitotic H4-K20 methylation and cytokinesis defects.","method":"siRNA depletion, Western blot for histone modifications, immunofluorescence, PR-Set7 overexpression rescue experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal loss-of-function and rescue experiments with defined chromatin modification readouts, single lab with multiple orthogonal methods","pmids":["15200950"],"is_preprint":false},{"year":2007,"finding":"During the G1-to-S phase transition, HCF-1 associates with both activator E2F1/E2F3a and repressor E2F4 proteins; when bound to E2F1, HCF-1 acts as a coactivator and recruits MLL and Set-1 histone H3K4 methyltransferases to E2F-responsive promoters, inducing histone methylation and transcriptional activation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), cell-cycle-staged cell fractionation, reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP at endogenous promoters, cell-cycle staging, replicated across species","pmids":["17612494"],"is_preprint":false},{"year":2009,"finding":"BAP1 deubiquitinase interacts with HCF-1N via an HCF-1 binding motif (HBM); BAP1 deubiquitinates Lys-48-linked polyubiquitin chains on the Kelch domain of HCF-1N; the HBM of BAP1 is required for both the HCF-1 interaction and BAP1-mediated growth regulation, and dominant-negative BAP1-mediated growth suppression is entirely dependent on the HBM.","method":"Mass spectrometry of co-purified proteins, co-immunoprecipitation, RNAi depletion, ubiquitin assays, HBM point mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS identification plus reciprocal co-IP plus functional mutagenesis, single lab","pmids":["19815555"],"is_preprint":false},{"year":2000,"finding":"HCF-1 contains two matched pairs of self-association sequences (SAS1 and SAS2) mediating HCF-1N:HCF-1C subunit association; SAS1 consists of a 43-aa HCF-1N region that associates with a tandem pair of fibronectin type 3 (Fn3) repeats in HCF-1C; HCF-1C subunits recruit HCF-1N subunits to the nucleus via a C-terminal nuclear localization signal.","method":"Domain deletion analysis, co-immunoprecipitation, nuclear localization assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping with functional validation, reciprocal co-IP, nuclear localization experiments, single lab with multiple methods","pmids":["10958670"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the HCF-1 self-association sequence 1 (SAS1) reveals an interdigitated fibronectin type 3 (Fn3) tandem repeat structure formed by SAS1 elements from HCF-1N and HCF-1C; the C-terminal nuclear localization signal (NLS) recruited by this structure is required for formation of the VP16-induced transcriptional regulatory complex.","method":"X-ray crystallography, mutagenesis of NLS, VP16-induced complex formation assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutagenesis validation, single lab","pmids":["23045687"],"is_preprint":false},{"year":2008,"finding":"C. elegans HCF-1 physically associates with the DAF-16/FOXO transcription factor; loss of hcf-1 causes daf-16-dependent lifespan extension and heightened stress resistance; HCF-1 limits DAF-16 recruitment to target gene promoters and thereby represses a subset of DAF-16-regulated genes.","method":"Co-immunoprecipitation, ChIP, genetic epistasis (daf-16 mutant suppression), lifespan assays, gene expression profiling","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, ChIP, and genetic epistasis with defined phenotypic readouts, replicated in follow-up studies","pmids":["18828672"],"is_preprint":false},{"year":2011,"finding":"C. elegans HCF-1 acts downstream of SIR-2.1 in lifespan regulation; SIR-2.1/SIRT1 and HCF-1 form protein complexes in both worms and mammalian cells; 80% overlap in DAF-16 target genes regulated by hcf-1 mutation and sir-2.1 overexpression; mammalian HCF-1 also represses FOXO/SIRT1 target genes, demonstrating conservation of this regulatory axis.","method":"Co-immunoprecipitation, genetic epistasis analysis, gene expression profiling, lifespan assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP in two species, genetic epistasis, transcriptome-wide overlap, functional conservation demonstrated","pmids":["21909281"],"is_preprint":false},{"year":2010,"finding":"THAP1 binds HCF-1 in vitro and associates with HCF-1 and OGT in vivo via a consensus HCF-1 binding motif (HBM); endogenous THAP1 mediates recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation; HCF-1 is essential for transcriptional activation of RRM1.","method":"Proteomic analysis, in vitro binding, co-immunoprecipitation, ChIP, RNAi knockdown, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus co-IP plus ChIP plus RNAi functional validation, single lab","pmids":["20200153"],"is_preprint":false},{"year":2010,"finding":"THAP11 (Ronin) binds with HCF-1 to a hyperconserved enhancer element at promoters of genes involved in transcription initiation, mRNA splicing, and cell metabolism in embryonic stem cells; Ronin/HCF-1 binding leads to both repression and activation of target genes essential for protein biosynthesis and energy production.","method":"ChIP-seq, co-immunoprecipitation, RNAi knockdown, gene expression profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq plus co-IP plus loss-of-function, single lab","pmids":["20581084"],"is_preprint":false},{"year":2013,"finding":"In HeLa cells, HCFC1 is bound to ~5,400 active CpG-island promoters; ZNF143, THAP11, YY1, and GABP transcription factors co-localize with HCFC1 at ~90% of HCFC1-bound promoters, revealing that a small set of sequence-specific factors directs HCFC1 to active promoters.","method":"ChIP-seq, motif analysis, co-localization analysis","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with motif validation, single lab, no direct interaction validation for all factors","pmids":["23539139"],"is_preprint":false},{"year":2002,"finding":"The highly conserved C-terminal WYF domain of HCF-1 interacts with the MYND domain of PDCD2; overexpression of PDCD2 suppresses HCF-1 complementation of the tsBN67 temperature-sensitive proliferation defect; expression of interfering domains of either protein enhances complementation, defining PDCD2 as a negative regulator of HCF-1C.","method":"Co-immunoprecipitation, domain mapping, tsBN67 cell complementation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional complementation assay, single lab","pmids":["12149646"],"is_preprint":false},{"year":2002,"finding":"HCF-1 is a component of spliceosomal complexes; it interacts with U1 and U5 splicing snRNPs; the tsBN67 HCF-1 missense mutation disrupts interaction with snRNPs at non-permissive temperature, causing inefficient spliceosome assembly and inhibition of splicing; restoration of wild-type HCF-1 rescues splicing.","method":"Co-immunoprecipitation with snRNPs, in vitro splicing assays in nuclear extracts, tsBN67 temperature-shift experiments, rescue by wild-type HCF-1 expression","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with snRNPs plus in vitro splicing assay plus genetic rescue, single lab","pmids":["12456665"],"is_preprint":false},{"year":2002,"finding":"HCF-1 contains an activation domain (HCF-1AD) in its C-terminal subunit required for maximal transactivation by VP16 and cellular LZIP; p300 augments HCF-1AD activity; cells lacking HCF-1AD show reduced HSV immediate-early gene expression and lower viral titers.","method":"Reporter gene assays, domain deletion/mutagenesis, infection assays, p300 co-expression","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain mapping with multiple transcription factor assays and viral infection readout, single lab","pmids":["12271126"],"is_preprint":false},{"year":2002,"finding":"HCF-1 beta-propeller domain binds a new cellular protein HPIP, which contains an HCF-binding motif and a leucine-rich nuclear export sequence; HPIP shuttles between nucleus and cytoplasm in a CRM1-dependent manner; HPIP overexpression leads to accumulation of HCF-1 in the cytoplasm, suggesting HPIP regulates HCF-1 subcellular localization.","method":"Co-immunoprecipitation, subcellular fractionation, CRM1 inhibition (leptomycin B), overexpression studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus CRM1-dependent export assay plus localization experiments, single lab","pmids":["12235138"],"is_preprint":false},{"year":2006,"finding":"The HCF-1 proteolytic processing domain interacts with FHL2 (four-and-a-half LIM domain-2); FHL2 interacts exclusively with the non-processed HCF-1 precursor; FHL2 and HCF-1 co-stimulate transcription of an HCF-1-dependent target gene; thus, site-specific proteolysis of HCF-1 regulates its interaction with FHL2 and modulates coactivator activity.","method":"Co-immunoprecipitation, reporter gene assay, domain analysis with processed vs. unprocessed HCF-1","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing processing-state selectivity plus functional reporter assay, single lab","pmids":["16624878"],"is_preprint":false},{"year":2010,"finding":"HCF-1 localizes to the Golgi apparatus in unstimulated sensory neurons; upon Golgi disruption, HCF-1 rapidly relocalizes to the nucleus, unlike other Golgi-associated proteins; this Golgi sequestration is distinct from the previously proposed ER/CREB3-mediated cytoplasmic retention, and nuclear relocalization correlates with viral reactivation.","method":"Immunofluorescence in primary neurons and latently infected mice, Golgi disruption experiments, subcellular localization studies","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in primary neurons with Golgi disruption assay, single lab","pmids":["18667495"],"is_preprint":false},{"year":2010,"finding":"HCF-1 interacts directly and simultaneously with both HSV DNA replication proteins and the cellular histone chaperone Asf1b; Asf1b localizes with HCF-1 at viral replication foci; depletion of Asf1b results in significantly reduced viral DNA accumulation, establishing HCF-1 as a component of the HSV DNA replication assembly that promotes viral DNA replication by coupling Asf1b to replication components.","method":"Co-immunoprecipitation (direct and simultaneous), immunofluorescence colocalization, siRNA depletion of Asf1b with viral DNA accumulation readout","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct and simultaneous co-IP plus localization plus siRNA functional assay, single lab","pmids":["20133788"],"is_preprint":false},{"year":2007,"finding":"Loss of the C. elegans HCF-1 homolog (Ce HCF-1) at reduced temperatures causes embryonic lethality with mitotic and cytokinetic defects; viable mutant embryos display reduced levels of phospho-histone H3 serine 10 (H3S10P); mammalian cells with defective HCF-1 also display defects in mitotic H3S10P status, indicating a conserved role for HCF-1 in regulating mitotic histone phosphorylation.","method":"C. elegans deletion mutant analysis, immunofluorescence for H3S10P in worms and mammalian cells, tsBN67 temperature-shift experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two model systems with defined histone modification readout, single lab","pmids":["18043729"],"is_preprint":false},{"year":2002,"finding":"Inactivation of pRb family members (pRb, p107, p130) by SV40 large T antigen or adenovirus E1A bypasses the requirement for HCF-1 function in tsBN67 cell proliferation and cytokinesis, without restoring HCF-1 chromatin association; this epistasis indicates that HCF-1 regulates cell proliferation and cytokinesis at least in part by opposing pRb family member function.","method":"Genetic epistasis using SV40 Tag and E1A, tsBN67 complementation assays, pRb family member mutants","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined molecular mechanism (pRb family inactivation), single lab","pmids":["12215534"],"is_preprint":false},{"year":2013,"finding":"Missense mutations in the HCFC1 Kelch domain cause X-linked cblX disorder; siRNA-mediated knockdown of HCFC1 in fibroblasts leads to coordinate downregulation of MMACHC mRNA; consensus HCFC1 binding sites were identified in the MMACHC promoter, establishing HCFC1 as a transcriptional regulator of MMACHC expression.","method":"siRNA knockdown, RT-PCR, promoter binding site analysis, patient fibroblast studies","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA functional assay plus promoter analysis in disease-relevant cells, single lab","pmids":["24011988"],"is_preprint":false},{"year":2014,"finding":"Zebrafish hcfc1b regulates cranial neural crest cell differentiation and proliferation within posterior pharyngeal arches; hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, establishing that HCFC1 acts upstream of MMACHC in craniofacial development.","method":"Zebrafish morpholino knockdown, rescue by MMACHC expression, analysis of neural crest cell differentiation/proliferation","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with specific downstream rescue experiment, single lab","pmids":["25281006"],"is_preprint":false},{"year":2019,"finding":"HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP; upon binding, HCF-1 recruits OGT to O-GlcNAcylate ChREBP and activate it; the HCF-1:ChREBP complex resides at lipogenic gene promoters where HCF-1 regulates H3K4 trimethylation and recruits the histone demethylase PHF2 for epigenetic activation of lipogenic genes.","method":"Co-immunoprecipitation, ChIP, O-GlcNAcylation assays, glucose-responsive cell culture experiments, genetic knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, ChIP, OGT-dependent modification assays, glucose-responsive experiments), mechanistically comprehensive, single lab","pmids":["31227231"],"is_preprint":false},{"year":2016,"finding":"OGT-mediated glycosylation and HCF-1 proteolysis occur through separable mechanisms within the same active site; a specific TPR domain contact with HCF-1 substrate is critical for proteolysis but not Ser/Thr glycosylation; key catalytic domain residues and UDP-GlcNAc oxygen important for glycosylation are irrelevant for proteolysis; single-activity OGT enzymes (either glycosylase-only or protease-only) can be engineered in vitro and in vivo.","method":"Active-site mutagenesis, in vitro glycosylation and proteolysis assays, engineered OGT variants","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with in vitro reconstitution of both activities, mechanistically definitive, single lab","pmids":["27056667"],"is_preprint":false},{"year":2015,"finding":"The HCF-1PRO repeat cleavage signal has specific OGT-binding properties; the glutamate at the cleavage site inhibits OGT:UDP-GlcNAc association; a novel OGT-binding sequence adjacent to the first HCF-1PRO repeat enhances cleavage, demonstrating that distinct OGT-binding sites in HCF-1 cooperate to promote proteolysis.","method":"In vitro OGT binding assays, mutagenesis of cleavage site glutamate, biochemical cleavage assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays with mutagenesis, single lab","pmids":["26305326"],"is_preprint":false},{"year":2018,"finding":"The HCF-1PRO repeat threonine-rich region is tightly bound by the OGT TPR region and activates both OGT glycosylation and proteolysis activities; linkage of this region to heterologous sequences potentiates serine glycosylation with poor OGT co-substrates and enables proteolysis of non-HCF-1PRO cleavage sequences containing an appropriately positioned glutamate.","method":"In vitro OGT glycosylation and proteolysis assays with chimeric substrates, mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with chimeric substrates and mutagenesis, single lab","pmids":["30224358"],"is_preprint":false},{"year":2009,"finding":"During the G1-to-S transition, E2F1 associates with HCF-1 through a short DHQY sequence; this HCF-1-binding sequence permits E2F1 to stimulate both DNA damage and apoptosis; HCF-1 and MLL family H3K4 methyltransferases have important functions in E2F1-mediated apoptosis; sequence changes in the E2F1 HCF-1-binding site modulate E2F1-induced apoptosis.","method":"Mutagenesis of E2F1 DHQY motif, co-immunoprecipitation, apoptosis assays, DNA damage assays, HCF-1 and MLL knockdown","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HBM mutagenesis plus co-IP plus functional apoptosis assay, single lab","pmids":["19763085"],"is_preprint":false},{"year":2003,"finding":"The HCF-1 binding motif (HBM) occurs in a wide spectrum of DNA-binding proteins and cofactors; Krox20 and E2F4 show strong requirement for functional HCF-1 to activate transcription; in Krox20, the HBM lies in the N-terminal activation domain and its mutation diminishes both transactivation and association with the HCF-1 beta-propeller; the HCF-1C activation domain contributes to Krox20-mediated activation, possibly through recruitment of p300.","method":"Reporter gene assays, co-immunoprecipitation, mutagenesis of HBM in Krox20","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus mutagenesis plus functional reporter assay, single lab","pmids":["14532282"],"is_preprint":false},{"year":2012,"finding":"THAP11 physically associates with HCF-1 and recruits HCF-1 to target gene promoters in colon cancer cells; THAP11-mediated gene regulation and chromatin association require HCF-1, while HCF-1 recruitment at THAP11 target genes requires THAP11, demonstrating mutual dependence.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown of THAP11 and HCF-1, gene expression profiling","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, ChIP, and double knockdown, single lab","pmids":["22371484"],"is_preprint":false},{"year":2015,"finding":"The THAP11/ZNF143/HCFC1 complex is recruited to chromatin through the ACTACA submotif shared by THAP11 and ZNF143; its position, spacing, and orientation relative to the ZNF143 core motif are critical for THAP11 and HCFC1 recruitment to ZNF143-occupied loci; CRISPR-Cas9-mediated alteration of the ACTACA submotif at endogenous promoters reduces THAP11 and HCFC1 binding and alters target gene transcription and histone modifications.","method":"CRISPR-Cas9 mutagenesis at endogenous promoters, synthetic chromatin-integrated constructs, ChIP, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR-Cas9 editing at endogenous loci plus synthetic constructs, multiple orthogonal methods, single lab","pmids":["26416877"],"is_preprint":false},{"year":2019,"finding":"HSP90 is required for the stability of nuclear HCFC1; HSP90 is required to maintain expression of HCFC1-targeted cell-cycle genes; HSP90 inhibition leads to HCFC1 degradation and consequent downregulation of cell-cycle gene expression.","method":"Three independent systematic analyses, biochemical co-immunoprecipitation, HSP90 inhibitor treatment, HCFC1 depletion with cell-cycle gene expression analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal approaches identifying HCFC1 as HSP90 client, functional validation of downstream gene expression, single lab","pmids":["31693902"],"is_preprint":false},{"year":2016,"finding":"HCF-1 conditional knockout in mouse hepatocytes demonstrates that HCF-1 is required for cell-cycle re-entry and proliferation in resting adult liver cells; HCF-1-deficient hepatocytes fail to re-enter the cell cycle during liver regeneration; in embryos, epiblast-specific HCF-1 loss causes cell-cycle exit and apoptosis of HCF-1-negative cells by E8.5.","method":"Cre-inducible conditional knockout mouse model, liver regeneration model, BrdU incorporation, apoptosis assays, X-chromosome inactivation analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout in two physiological contexts (embryo and adult liver regeneration), defined cellular and molecular phenotypes","pmids":["26921005"],"is_preprint":false},{"year":2016,"finding":"Complete epiblast-specific loss of HCF-1 in male embryos leads to developmental arrest at E6.5 with rapid progressive cell-cycle exit, failure of anterior visceral endoderm migration, failure of primitive streak formation, and absence of gastrulation; the pattern of lethality resembles loss of β-catenin function.","method":"Conditional knockout mouse model (Hcfc1 epiKO/Y), developmental staging, immunohistochemistry, cell-cycle analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with staged developmental analysis and defined molecular markers, single lab","pmids":["27521049"],"is_preprint":false},{"year":2021,"finding":"SETD5 regulates RNA polymerase II promoter-proximal pausing on E2F target genes in hematopoietic stem cells in cooperation with HCF-1 and the PAF1 complex; loss of Setd5 disrupts HSC quiescence; HCF-1 co-immunoprecipitates with SETD5.","method":"Co-immunoprecipitation of SETD5 and HCF-1, conditional knockout mouse model, Pol II ChIP, transcriptome analysis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus in vivo KO, single lab; HCF-1 role is partly inferred from the co-IP and shared target gene regulation","pmids":["34853439"],"is_preprint":false},{"year":2020,"finding":"HCF-1 activates CDC42 expression by binding to the -881 to -575 region upstream of the CDC42 transcription start site; overexpression of constitutively active CDC42F28L rescues G1 phase delay and multinucleate defects caused by HCF-1 loss, establishing CDC42 as a functional downstream target of HCF-1 in cell cycle progression.","method":"ChIP to the CDC42 promoter, siRNA depletion of HCF-1, rescue by constitutively active CDC42, cell cycle and multinucleation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific promoter region plus functional rescue experiment, single lab","pmids":["33097698"],"is_preprint":false},{"year":2013,"finding":"HCF-1 is required for INS-1 pancreatic β-cell glucose-stimulated insulin secretion; HCF-1 reduction causes decreased expression of Pdx1; HCF-1 and E2F1 co-localize at the Pdx1 promoter as shown by ChIP.","method":"siRNA knockdown, glucose-stimulated insulin secretion assay, RT-PCR for Pdx1, ChIP","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at Pdx1 promoter plus functional insulin secretion assay, single lab","pmids":["24250814"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, HCF-1 chromatin localization is largely dependent on functional SET-26; SET-26 and HCF-1 cooperate to regulate a common set of target genes; the histone deacetylase HDA-1 opposes both SET-26 and HCF-1 at a subset of shared target genes and in longevity regulation.","method":"ChIP, genetic epistasis (set-26, hcf-1, hda-1 mutants), gene expression profiling, lifespan assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic epistasis with transcriptomic validation, single lab","pmids":["38485937"],"is_preprint":false},{"year":2022,"finding":"Mouse models of Hcfc1 mutation exhibit reduced expression of MMACHC (confirming transcriptional regulation) and additionally show reduced expression of ribosomal protein subunit genes; developmental defects associated with these mutations include aspects of both cblC and ribosomopathies, identifying HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development.","method":"Mouse conditional knockout models, RNA-seq, metabolic analysis, developmental phenotyping","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models with transcriptomic profiling, single lab","pmids":["35013307"],"is_preprint":false},{"year":2023,"finding":"Conditional deletion of HCF-1 in sensory neurons in vivo causes a striking reduction in latently infected neurons that initiate HSV-1 reactivation; this correlated with a defect in removal of repressive heterochromatin from latent viral genomes, establishing HCF-1 as a critical in vivo regulator that promotes the transition of latent HSV genomes from a repressed chromatin state.","method":"HCF-1 conditional knockout mouse model, HSV latency/reactivation model, ChIP for repressive chromatin marks, viral reactivation quantification","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with ChIP chromatin analysis and viral reactivation readout, single lab but first in vivo demonstration","pmids":["36692302"],"is_preprint":false},{"year":2025,"finding":"Hepatocyte-specific HCF-1 deletion leads to progressive loss of OGT protein levels and global O-GlcNAcylation without altering OGT mRNA, indicating post-translational regulation of OGT stability by HCF-1; loss of HCF-1 reduces nuclear OGT and O-GlcNAcylation, mimicking fasting conditions; HCF-1-negative hepatocytes display cytoplasmic O-GlcNAcylation while HCF-1-positive cells maintain nuclear localization.","method":"Hepatocyte-specific conditional knockout mouse, immunofluorescence, Western blot, OGT mRNA analysis, fractionation studies","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with multi-method validation of OGT stability and localization, single lab","pmids":["40754593"],"is_preprint":false},{"year":2026,"finding":"HCF-1 is required for neuronal differentiation and forebrain commissure formation; HCF-1 directly occupies promoters of key neuronal genes (Elavl3, NeuroD1) and its loss reduces activating chromatin marks at these loci; OGT inhibition phenocopies HCF-1 depletion in impairing neuronal proliferation, differentiation, and neurite outgrowth; glycoproteomic analysis reveals disruption of OGT-dependent protein networks involved in neuronal structure.","method":"Conditional neuronal knockout, ChIP at neuronal gene promoters, siRNA depletion, OGT inhibitor (OSMI-1), glycoproteomics, transcriptomics","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO plus ChIP plus OGT inhibitor phenocopy, single lab","pmids":["41651253"],"is_preprint":false},{"year":2026,"finding":"HCF-1 binds to the C-terminal ~200 amino acids of ASXL1 and promotes ASXL1 proteasome-dependent turnover; deletion of this ASXL1 C-terminal region abrogates HCF-1 binding and stabilizes ASXL1; HCF-1 and BAP1 show reciprocal antagonism in association with ASXL1, suggesting indirect coupling in complex assembly.","method":"P2A dual-reporter stability assay, co-immunoprecipitation, proteasome inhibitor experiments, domain deletion mapping","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping plus functional stability assay plus BAP1 competition, single lab","pmids":["41968849"],"is_preprint":false},{"year":2024,"finding":"KDM2A recruits E2F1 and HCFC1 to promoters of key meiosis genes (Stra8, Meiosin, Spo11, Sycp1) in male germ cells; conditional deletion of Kdm2a disrupts H3K36me2/3 deposition and impairs expression of HCFC1-recruited target genes required for meiotic entry and progression.","method":"Co-immunoprecipitation of KDM2A-E2F1-HCFC1, ChIP at meiotic gene promoters, conditional knockout mouse, H3K36me2/3 analysis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus in vivo KO, single lab; HCFC1 role shown as part of KDM2A complex","pmids":["39160277"],"is_preprint":false},{"year":1999,"finding":"A second HCF-like protein HCF-2 was identified; chimeric protein analysis showed that differences between the fifth and sixth kelch repeats of the beta-propeller domains of HCF-1 and HCF-2 determine selective recruitment of HCF-1 over HCF-2 by VP16 and LZIP.","method":"Chimeric protein construction, in vitro binding assays, VP16-induced complex assembly assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric protein domain swapping with functional complex assembly assays, single lab","pmids":["10196288"],"is_preprint":false},{"year":2025,"finding":"RONIN (THAP11) modulates TFEB transcriptional activity through its interaction with HCF-1/HCFC1; RONIN overexpression improved autophagy levels, lysosomal activity, and attenuated D-galactose-induced hair cell senescence, working through TFEB activation.","method":"Co-immunoprecipitation of RONIN and HCF1, overexpression studies, autophagy/lysosomal activity assays, hair cell senescence model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional overexpression with autophagy readout, single lab","pmids":["39985193"],"is_preprint":false},{"year":2024,"finding":"HSP90 N-terminal inhibition reduces HCFC1 protein levels, preventing HCFC1 from binding to the TFEB proximal promoter; decreased TFEB transcription then reduces LC3 levels and promotes mitochondria-derived vesicle (MDV) formation and tumor metastasis; re-activation of the HCFC1-TFEB-LC3 axis by blocking MDV formation suppresses metastasis.","method":"ChIP for HCFC1 at TFEB promoter, HSP90 inhibitor treatment, HSP90AA1-HCFC1 co-immunoprecipitation, TFEB/LC3 Western blot, MDV formation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at TFEB promoter plus co-IP plus functional metabolic assays, single lab","pmids":["39461872"],"is_preprint":false}],"current_model":"HCFC1 (HCF-1) is a metazoan transcriptional co-regulator that undergoes OGT-catalyzed proteolytic maturation at centrally located HCF-1PRO repeats (occurring within the OGT glycosyltransferase active site via a glutamate cleavage mechanism), generating stably associated HCF-1N and HCF-1C subunits that control distinct cell-cycle phases: HCF-1N promotes G1/S progression by associating with E2F1, THAP11, ZNF143, and other sequence-specific factors to recruit MLL/Set1 H3K4 methyltransferases and Sin3 HDAC to target promoters, while HCF-1C ensures proper M-phase exit and cytokinesis by regulating PR-Set7 and H4-K20 methylation status; additionally, HCF-1 is O-GlcNAcylated by OGT in a nutrient-responsive manner that gates its interaction with ChREBP to epigenetically activate lipogenic genes, it is stabilized by HSP90 in the nucleus, its subcellular localization is regulated (Golgi sequestration in neurons, CRM1-dependent cytoplasmic export via HPIP) to gate herpesvirus reactivation, and BAP1 deubiquitinates HCF-1N Lys-48 polyubiquitin chains to modulate HCF-1-dependent proliferation."},"narrative":{"mechanistic_narrative":"HCFC1 (HCF-1) is a chromatin-associated transcriptional co-regulator that couples sequence-specific DNA-binding factors to histone-modifying machinery to control cell proliferation, cell-cycle progression, and developmental gene programs [PMID:12670868, PMID:12743030]. It is synthesized as a precursor that undergoes site-specific proteolytic maturation by O-GlcNAc transferase (OGT) at centrally located HCF-1PRO repeats, generating an HCF-1N and an HCF-1C subunit that remain associated through interdigitated fibronectin type-3 (SAS1/SAS2) elements and a C-terminal nuclear localization signal [PMID:21295698, PMID:10958670, PMID:23045687]. Structural and biochemical work established that OGT engages the HCF-1PRO repeat via its TPR domain, positions the cleavage region in the glycosyltransferase active site, and cleaves between cysteine and glutamate to yield a pyroglutamate product, with glycosylation and proteolysis being mechanistically separable activities of the same active site [PMID:24311690, PMID:27056667]. The two subunits perform distinct cell-cycle roles: HCF-1N promotes G1/S progression, recruiting MLL/Set1 H3K4 methyltransferases and the Sin3 HDAC complex to target promoters together with sequence-specific factors such as E2F1, while HCF-1C ensures proper mitotic exit and cytokinesis, in part by regulating the H4-K20 methyltransferase PR-Set7 and mitotic histone modification status [PMID:12670868, PMID:12743030, PMID:15200950, PMID:17612494]. HCF-1 is targeted to thousands of active promoters by a small set of partner factors — notably THAP11, ZNF143, and E2F family proteins binding via an HCF-1 binding motif (HBM) and shared submotifs — to direct transcription of cell-cycle, biosynthetic, and metabolic genes [PMID:20581084, PMID:23539139, PMID:26416877], including direct activation of CDC42 [PMID:33097698]. Its activity is gated by post-translational and metabolic inputs: glucose-stimulated O-GlcNAcylation licenses binding to ChREBP for epigenetic activation of lipogenic genes [PMID:31227231], HSP90 maintains nuclear HCF-1 stability and expression of its cell-cycle target genes [PMID:31693902], and BAP1 deubiquitinates Lys-48 chains on the HCF-1N Kelch domain to modulate proliferation [PMID:19815555]. In vivo, HCF-1 is required for cell-cycle re-entry and proliferation in regenerating liver and for epiblast survival and gastrulation [PMID:26921005, PMID:27521049], and it promotes herpesvirus reactivation by driving removal of repressive heterochromatin from latent viral genomes [PMID:36692302]. Missense mutations in the HCFC1 Kelch domain cause X-linked cblX disorder, linked to loss of HCFC1-driven MMACHC transcription [PMID:24011988].","teleology":[{"year":2000,"claim":"Established the structural logic of subunit association, answering how the two HCF-1 fragments remain a functional unit after processing.","evidence":"Domain deletion, co-IP, and nuclear localization assays defining SAS1/SAS2 and the C-terminal NLS","pmids":["10958670"],"confidence":"High","gaps":["Did not resolve how processing is triggered","Atomic structure of the interface not yet defined at this stage"]},{"year":2001,"claim":"Showed that HCF-1 chromatin association through its Kelch/beta-propeller domain is required for proliferation, linking a binding activity to a proliferative function.","evidence":"Chromatin fractionation and temperature-shift in tsBN67 cells","pmids":["11340173"],"confidence":"High","gaps":["Did not identify the chromatin-tethering partner factors","Mechanism connecting chromatin loss to arrest unresolved"]},{"year":2002,"claim":"Connected HCF-1 to multiple regulatory contexts — spliceosomal snRNPs, a C-terminal activation domain augmented by p300, the pRb pathway, and HPIP-mediated CRM1 export — broadening its functional reach beyond a single coactivator role.","evidence":"Co-IP, in vitro splicing, reporter assays, genetic epistasis, and CRM1-inhibition localization studies","pmids":["12456665","12271126","12215534","12235138","12149646"],"confidence":"Medium","gaps":["Splicing role not integrated with transcriptional functions","Physiological significance of cytoplasmic export incompletely defined"]},{"year":2003,"claim":"Defined the two-subunit, two-cell-cycle-stage model and the histone-modifier tethering function, establishing HCF-1 as a bifunctional cell-cycle regulator.","evidence":"siRNA depletion across cell lines with cell-cycle/cytokinesis readouts, co-IP and domain mapping of Sin3 and Set1/Ash2 complexes, and HBM analysis across DNA-binding proteins","pmids":["12743030","12670868","14532282"],"confidence":"High","gaps":["Did not explain how proteolysis separates the two functions mechanistically","Promoter-level target genes not yet genome-wide"]},{"year":2004,"claim":"Identified PR-Set7/H4-K20 methylation control as the molecular basis of HCF-1C mitotic function, linking the C-subunit to chromosome segregation.","evidence":"siRNA depletion, histone modification Westerns, and PR-Set7 overexpression rescue","pmids":["15200950"],"confidence":"High","gaps":["Mechanism by which HCF-1C controls PR-Set7 expression unresolved"]},{"year":2007,"claim":"Mapped HCF-1's G1/S coactivator mechanism onto E2F factors and conserved mitotic H3S10 phosphorylation control, defining its proliferative gene-activation route.","evidence":"Co-IP, ChIP at E2F promoters, cell-cycle staging, and C. elegans/mammalian H3S10P analysis","pmids":["17612494","18043729"],"confidence":"High","gaps":["How HCF-1 switches between E2F activator and repressor complexes not fully defined"]},{"year":2008,"claim":"Revealed a conserved repressive role for HCF-1 on FOXO/DAF-16 signaling and lifespan, extending its function to stress and longevity regulation.","evidence":"C. elegans co-IP, ChIP, genetic epistasis, and lifespan assays; extended with SIR-2.1 epistasis and conservation in mammals","pmids":["18828672","21909281"],"confidence":"High","gaps":["Direct chromatin mechanism of DAF-16 repression not fully resolved","Mammalian longevity relevance only inferred from target-gene overlap"]},{"year":2010,"claim":"Established HCF-1's promoter-targeting partners (THAP1, THAP11/Ronin) and its direct participation in HSV DNA replication and Golgi-gated localization, integrating recruitment and viral life-cycle control.","evidence":"Proteomics, in vitro binding, co-IP, ChIP, ChIP-seq in ESCs, immunofluorescence in neurons, and Asf1b depletion with viral DNA readouts","pmids":["20200153","20581084","20133788","18667495"],"confidence":"High","gaps":["Signal triggering Golgi-to-nucleus relocalization undefined","How a single factor coordinates host transcription and viral replication unclear"]},{"year":2011,"claim":"Resolved that OGT is the protease that cleaves HCF-1 and that cleavage per se, not merely fragment separation, is required for HCF-1C function, unifying glycosylation and maturation under one enzyme.","evidence":"In vitro OGT cleavage assays, HCF-1PRO mutagenesis, and cell-based M-phase assays","pmids":["21295698"],"confidence":"High","gaps":["Structural basis of cleavage not yet determined at this stage"]},{"year":2013,"claim":"Provided the structural and genome-wide mechanism: how OGT positions and cleaves the PRO repeat, and how a few sequence-specific factors direct HCFC1 to thousands of active promoters, plus the disease link to cblX.","evidence":"Crystal structure of OGT:HCF-1PRO complex with active-site mutagenesis; ChIP-seq with motif/co-localization analysis; patient mutation and MMACHC promoter studies","pmids":["24311690","23539139","24011988"],"confidence":"High","gaps":["Whether all co-localizing factors bind HCFC1 directly not validated","How cblX mutations alter chromatin engagement not structurally resolved"]},{"year":2016,"claim":"Demonstrated in vivo requirement for HCF-1 in proliferation and development and dissected OGT's dual glycosylation/proteolysis activities into separable mechanisms.","evidence":"Conditional knockout in mouse hepatocytes/epiblast; active-site mutagenesis and engineered single-activity OGT variants","pmids":["26921005","27521049","27056667"],"confidence":"High","gaps":["Direct transcriptional targets driving embryonic/regenerative phenotypes not fully mapped"]},{"year":2019,"claim":"Linked HCF-1 to nutrient-responsive metabolic transcription and to HSP90-dependent stability, showing how its activity and abundance are gated by upstream signals.","evidence":"Glucose-responsive co-IP/ChIP/O-GlcNAc assays for ChREBP; HSP90 inhibition with HCFC1 degradation and cell-cycle gene readouts","pmids":["31227231","31693902"],"confidence":"High","gaps":["Whether metabolic and cell-cycle programs are regulated by the same HCF-1 pool unclear"]},{"year":2024,"claim":"Extended the promoter-recruitment and tissue-specific roles of HCF-1 to ribosome biogenesis, meiotic entry, neuronal differentiation, and OGT stability, defining context-specific gene programs.","evidence":"Mouse conditional knockouts with RNA-seq, ChIP at meiotic/neuronal/MMACHC/ribosomal loci, KDM2A and SET-26 co-IP/epistasis, and OGT inhibitor phenocopy","pmids":["35013307","39160277","41651253","40754593","38485937"],"confidence":"Medium","gaps":["Whether these tissue programs share a common HCF-1 mechanism unresolved","Direct vs complex-mediated recruitment in several contexts inferred from co-IP"]},{"year":2025,"claim":"Connected HCF-1 to autophagy/lysosomal control via TFEB transcription and to protein-stability regulation of ASXL1, broadening its regulatory outputs.","evidence":"Co-IP and overexpression with autophagy/lysosomal and senescence readouts; ChIP at TFEB promoter; stability/co-IP assays for ASXL1 with BAP1 competition","pmids":["39985193","39461872","41968849"],"confidence":"Medium","gaps":["TFEB axis mostly shown via overexpression/inhibitor perturbation","Functional consequence of HCF-1-driven ASXL1 turnover in vivo undefined"]},{"year":null,"claim":"How HCF-1 selects among its many partner factors and chromatin-modifier complexes to execute distinct programs (G1/S vs mitosis, proliferation vs lipogenesis vs autophagy) in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of partner-selection logic","Quantitative contribution of OGT-cleavage, O-GlcNAcylation, HSP90, and BAP1 to context-specific outputs not integrated","Structural basis of full HCF-1N:HCF-1C:partner assemblies on chromatin lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,6,26,38]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[24,38,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,45]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,34]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,14,42]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,6,35]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,13,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,26,33]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[35,36,25,44]}],"complexes":["Set1/Ash2 H3K4 methyltransferase complex","Sin3 HDAC complex","THAP11/ZNF143/HCFC1 complex"],"partners":["OGT","THAP11","ZNF143","E2F1","BAP1","HSP90","CHREBP","ASXL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51610","full_name":"Host cell factor 1","aliases":["C1 factor","CFF","VCAF","VP16 accessory protein"],"length_aa":2035,"mass_kda":208.7,"function":"Transcriptional coregulator (By similarity). Serves as a scaffold protein, bridging interactions between transcription factors, including THAP11 and ZNF143, and transcriptional coregulators (PubMed:26416877). Involved in control of the cell cycle (PubMed:10629049, PubMed:10779346, PubMed:15190068, PubMed:16624878, PubMed:23629655). Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300 (PubMed:10675337, PubMed:12244100). Coactivator for EGR2 and GABP2 (PubMed:12244100, PubMed:14532282). Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together (PubMed:12670868). Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1 (PubMed:20200153). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues (PubMed:20018852). Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition (PubMed:23629655). Modulates expression of homeobox protein PDX1, perhaps acting in concert with transcription factor E2F1, thereby regulating pancreatic beta-cell growth and glucose-stimulated insulin secretion (By similarity). May negatively modulate transcriptional activity of FOXO3 (By similarity) (Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P51610/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HCFC1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATG13","stoichiometry":0.2},{"gene":"CBX1","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HCFC1","total_profiled":1310},"omim":[{"mim_id":"621243","title":"TRANSCRIPTION ACTIVATION SUPPRESSOR FAMILY, MEMBER 2; TASOR2","url":"https://www.omim.org/entry/621243"},{"mim_id":"620940","title":"METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblL TYPE; MAHCL","url":"https://www.omim.org/entry/620940"},{"mim_id":"618818","title":"HOST CELL FACTOR C1 REGULATOR 1; HCFC1R1","url":"https://www.omim.org/entry/618818"},{"mim_id":"617109","title":"CREB3 RECRUITMENT FACTOR; CREBRF","url":"https://www.omim.org/entry/617109"},{"mim_id":"615488","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 2; KANSL2","url":"https://www.omim.org/entry/615488"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HCFC1"},"hgnc":{"alias_symbol":["HCF-1","HCF1","CFF","VCAF","MGC70925","PPP1R89"],"prev_symbol":["HFC1","MRX3"]},"alphafold":{"accession":"P51610","domains":[{"cath_id":"2.120.10.80","chopping":"19-279_289-363","consensus_level":"medium","plddt":91.3089,"start":19,"end":363},{"cath_id":"2.60.40.10","chopping":"364-403_1811-1833_1851-1888","consensus_level":"medium","plddt":91.038,"start":364,"end":1888},{"cath_id":"2.60.40.10","chopping":"1896-1933_1947-2000","consensus_level":"high","plddt":86.1564,"start":1896,"end":2000}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51610","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51610-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51610-F1-predicted_aligned_error_v6.png","plddt_mean":46.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HCFC1","jax_strain_url":"https://www.jax.org/strain/search?query=HCFC1"},"sequence":{"accession":"P51610","fasta_url":"https://rest.uniprot.org/uniprotkb/P51610.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51610/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51610"}},"corpus_meta":[{"pmid":"12670868","id":"PMC_12670868","title":"Human 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Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41018975","citation_count":2,"is_preprint":false},{"pmid":"35047725","id":"PMC_35047725","title":"THE APPLICATION OF CELL-FREE FETAL DNA (cff-DNA) AND SIBLINGS DNA METHODS IN THE PROCESS OF PATERNITY TEST THROUGH CODIS STR LOCI (CSF1PO, THO1, TPOX, AND vWA).","date":"2021","source":"African journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35047725","citation_count":2,"is_preprint":false},{"pmid":"38596069","id":"PMC_38596069","title":"Key chromatin regulator-related genes associated with the risk of coronary artery disease regulate the expression of HCFC1, RNF8, TNP1 and SET.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38596069","citation_count":2,"is_preprint":false},{"pmid":"8661027","id":"PMC_8661027","title":"The complete sequence of the host cell factor 1 (HCFC1) gene and its promoter: a role for YY1 transcription factor in the regulation of its expression.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8661027","citation_count":2,"is_preprint":false},{"pmid":"41108067","id":"PMC_41108067","title":"Hcfc1 and Ogt Mediate Zebrafish CNS Regeneration Through Hippo/Yap Signalling.","date":"2025","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/41108067","citation_count":1,"is_preprint":false},{"pmid":"36993207","id":"PMC_36993207","title":"The chromatin factors SET-26 and HCF-1 oppose the histone deacetylase HDA-1 in longevity and gene regulation in C. elegans.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36993207","citation_count":1,"is_preprint":false},{"pmid":"29726666","id":"PMC_29726666","title":"[Chinese medicinal compound CFF-1 induces the apoptosis and cycle-arrest of prostate cancer cells via the PI3K/AKT/FOXO1 signaling pathway].","date":"2017","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/29726666","citation_count":1,"is_preprint":false},{"pmid":"41651253","id":"PMC_41651253","title":"The HCF-1:OGT axis regulates neuronal proliferation and differentiation.","date":"2026","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/41651253","citation_count":0,"is_preprint":false},{"pmid":"41161405","id":"PMC_41161405","title":"The IRβ/HCF-1/ChREBP axis: A new paradigm in insulin-regulated hepatic lipogenesis.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41161405","citation_count":0,"is_preprint":false},{"pmid":"41968849","id":"PMC_41968849","title":"A Degron-Like Regulatory Region in the ASXL1 C-Terminal Domain Mediates HCF-1-Dependent Regulation of Protein Stability.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41968849","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48230,"output_tokens":12436,"usd":0.165615,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23456,"output_tokens":5226,"usd":0.123965,"stage2_stop_reason":"end_turn"},"total_usd":0.28958,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Separate regions of HCF-1 critical for cell proliferation associate with the Sin3 histone deacetylase (HDAC) complex and a human trithorax-related Set1/Ash2 histone H3-K4 methyltransferase (HMT) complex; HCF-1 tethers these two complexes together, and the transcriptional activator VP16 selectively binds HCF-1 associated with the Set1/Ash2 HMT complex in the absence of the Sin3 HDAC complex.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, in vitro binding assays, domain mapping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain mapping, multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"12670868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HCF-1 is naturally bound to chromatin in uninfected cells through its VP16 interaction domain (Kelch/beta-propeller domain); dissociation from chromatin in tsBN67 cells precedes and causes temperature-induced cell proliferation arrest.\",\n      \"method\": \"Chromatin fractionation, temperature-shift experiments, tsBN67 cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, direct fractionation with functional correlation, replicated across studies\",\n      \"pmids\": [\"11340173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"O-GlcNAc transferase (OGT) both O-GlcNAcylates the HCF-1N subunit and directly cleaves HCF-1 at the HCF-1PRO repeat sequences, performing site-specific proteolytic maturation; replacement of HCF-1PRO repeats with a heterologous cleavage signal promotes proteolysis but fails to activate HCF-1C M-phase functions, showing that OGT-mediated cleavage is specifically required for HCF-1C function.\",\n      \"method\": \"In vitro OGT cleavage assays, mutagenesis of HCF-1PRO repeats, cell-based M-phase progression assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with in vitro cleavage, mutagenesis, and functional cell-based validation in one rigorous study\",\n      \"pmids\": [\"21295698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The tetratricopeptide-repeat (TPR) domain of OGT binds the C-terminal portion of an HCF-1 proteolytic repeat, positioning the cleavage region in the glycosyltransferase active site above UDP-GlcNAc; cleavage occurs between cysteine and glutamate residues producing a pyroglutamate product; mutation of the cleavage-site glutamate to serine converts an HCF-1 proteolytic repeat into a glycosylation substrate.\",\n      \"method\": \"Crystal structure of OGT:HCF-1PRO-repeat complex, active-site mutagenesis, biochemical cleavage assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus active-site mutagenesis plus in vitro biochemical validation\",\n      \"pmids\": [\"24311690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HCF-1 regulates two distinct stages of the cell cycle via its two proteolytically generated subunits: HCF-1N promotes G1-phase progression, while HCF-1C ensures proper cytokinesis/exit from mitosis; siRNA depletion of HCF-1 in diverse mammalian cells caused both G1 arrest and cytokinesis defects, and proteolytic processing is required to separate and ensure these functions.\",\n      \"method\": \"siRNA knockdown in multiple mammalian cell lines, cell-cycle analysis, cytokinesis assays, expression of separated subunits\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function across multiple cell types with defined phenotypic readouts, replicated in multiple studies\",\n      \"pmids\": [\"12743030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Depletion of the HCF-1C subunit causes mitotic defects including a switch from monomethyl to dimethyl H4-K20 and defective chromosome alignment/segregation; HCF-1C regulates expression of the H4-K20 methyltransferase PR-Set7, and upregulation of PR-Set7 upon HCF-1 loss leads to improper mitotic H4-K20 methylation and cytokinesis defects.\",\n      \"method\": \"siRNA depletion, Western blot for histone modifications, immunofluorescence, PR-Set7 overexpression rescue experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss-of-function and rescue experiments with defined chromatin modification readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15200950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"During the G1-to-S phase transition, HCF-1 associates with both activator E2F1/E2F3a and repressor E2F4 proteins; when bound to E2F1, HCF-1 acts as a coactivator and recruits MLL and Set-1 histone H3K4 methyltransferases to E2F-responsive promoters, inducing histone methylation and transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), cell-cycle-staged cell fractionation, reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP at endogenous promoters, cell-cycle staging, replicated across species\",\n      \"pmids\": [\"17612494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BAP1 deubiquitinase interacts with HCF-1N via an HCF-1 binding motif (HBM); BAP1 deubiquitinates Lys-48-linked polyubiquitin chains on the Kelch domain of HCF-1N; the HBM of BAP1 is required for both the HCF-1 interaction and BAP1-mediated growth regulation, and dominant-negative BAP1-mediated growth suppression is entirely dependent on the HBM.\",\n      \"method\": \"Mass spectrometry of co-purified proteins, co-immunoprecipitation, RNAi depletion, ubiquitin assays, HBM point mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus reciprocal co-IP plus functional mutagenesis, single lab\",\n      \"pmids\": [\"19815555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HCF-1 contains two matched pairs of self-association sequences (SAS1 and SAS2) mediating HCF-1N:HCF-1C subunit association; SAS1 consists of a 43-aa HCF-1N region that associates with a tandem pair of fibronectin type 3 (Fn3) repeats in HCF-1C; HCF-1C subunits recruit HCF-1N subunits to the nucleus via a C-terminal nuclear localization signal.\",\n      \"method\": \"Domain deletion analysis, co-immunoprecipitation, nuclear localization assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with functional validation, reciprocal co-IP, nuclear localization experiments, single lab with multiple methods\",\n      \"pmids\": [\"10958670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the HCF-1 self-association sequence 1 (SAS1) reveals an interdigitated fibronectin type 3 (Fn3) tandem repeat structure formed by SAS1 elements from HCF-1N and HCF-1C; the C-terminal nuclear localization signal (NLS) recruited by this structure is required for formation of the VP16-induced transcriptional regulatory complex.\",\n      \"method\": \"X-ray crystallography, mutagenesis of NLS, VP16-induced complex formation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutagenesis validation, single lab\",\n      \"pmids\": [\"23045687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"C. elegans HCF-1 physically associates with the DAF-16/FOXO transcription factor; loss of hcf-1 causes daf-16-dependent lifespan extension and heightened stress resistance; HCF-1 limits DAF-16 recruitment to target gene promoters and thereby represses a subset of DAF-16-regulated genes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, genetic epistasis (daf-16 mutant suppression), lifespan assays, gene expression profiling\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, ChIP, and genetic epistasis with defined phenotypic readouts, replicated in follow-up studies\",\n      \"pmids\": [\"18828672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans HCF-1 acts downstream of SIR-2.1 in lifespan regulation; SIR-2.1/SIRT1 and HCF-1 form protein complexes in both worms and mammalian cells; 80% overlap in DAF-16 target genes regulated by hcf-1 mutation and sir-2.1 overexpression; mammalian HCF-1 also represses FOXO/SIRT1 target genes, demonstrating conservation of this regulatory axis.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis analysis, gene expression profiling, lifespan assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP in two species, genetic epistasis, transcriptome-wide overlap, functional conservation demonstrated\",\n      \"pmids\": [\"21909281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"THAP1 binds HCF-1 in vitro and associates with HCF-1 and OGT in vivo via a consensus HCF-1 binding motif (HBM); endogenous THAP1 mediates recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation; HCF-1 is essential for transcriptional activation of RRM1.\",\n      \"method\": \"Proteomic analysis, in vitro binding, co-immunoprecipitation, ChIP, RNAi knockdown, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus co-IP plus ChIP plus RNAi functional validation, single lab\",\n      \"pmids\": [\"20200153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"THAP11 (Ronin) binds with HCF-1 to a hyperconserved enhancer element at promoters of genes involved in transcription initiation, mRNA splicing, and cell metabolism in embryonic stem cells; Ronin/HCF-1 binding leads to both repression and activation of target genes essential for protein biosynthesis and energy production.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, RNAi knockdown, gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq plus co-IP plus loss-of-function, single lab\",\n      \"pmids\": [\"20581084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In HeLa cells, HCFC1 is bound to ~5,400 active CpG-island promoters; ZNF143, THAP11, YY1, and GABP transcription factors co-localize with HCFC1 at ~90% of HCFC1-bound promoters, revealing that a small set of sequence-specific factors directs HCFC1 to active promoters.\",\n      \"method\": \"ChIP-seq, motif analysis, co-localization analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with motif validation, single lab, no direct interaction validation for all factors\",\n      \"pmids\": [\"23539139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The highly conserved C-terminal WYF domain of HCF-1 interacts with the MYND domain of PDCD2; overexpression of PDCD2 suppresses HCF-1 complementation of the tsBN67 temperature-sensitive proliferation defect; expression of interfering domains of either protein enhances complementation, defining PDCD2 as a negative regulator of HCF-1C.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, tsBN67 cell complementation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional complementation assay, single lab\",\n      \"pmids\": [\"12149646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HCF-1 is a component of spliceosomal complexes; it interacts with U1 and U5 splicing snRNPs; the tsBN67 HCF-1 missense mutation disrupts interaction with snRNPs at non-permissive temperature, causing inefficient spliceosome assembly and inhibition of splicing; restoration of wild-type HCF-1 rescues splicing.\",\n      \"method\": \"Co-immunoprecipitation with snRNPs, in vitro splicing assays in nuclear extracts, tsBN67 temperature-shift experiments, rescue by wild-type HCF-1 expression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with snRNPs plus in vitro splicing assay plus genetic rescue, single lab\",\n      \"pmids\": [\"12456665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HCF-1 contains an activation domain (HCF-1AD) in its C-terminal subunit required for maximal transactivation by VP16 and cellular LZIP; p300 augments HCF-1AD activity; cells lacking HCF-1AD show reduced HSV immediate-early gene expression and lower viral titers.\",\n      \"method\": \"Reporter gene assays, domain deletion/mutagenesis, infection assays, p300 co-expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain mapping with multiple transcription factor assays and viral infection readout, single lab\",\n      \"pmids\": [\"12271126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HCF-1 beta-propeller domain binds a new cellular protein HPIP, which contains an HCF-binding motif and a leucine-rich nuclear export sequence; HPIP shuttles between nucleus and cytoplasm in a CRM1-dependent manner; HPIP overexpression leads to accumulation of HCF-1 in the cytoplasm, suggesting HPIP regulates HCF-1 subcellular localization.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, CRM1 inhibition (leptomycin B), overexpression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus CRM1-dependent export assay plus localization experiments, single lab\",\n      \"pmids\": [\"12235138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The HCF-1 proteolytic processing domain interacts with FHL2 (four-and-a-half LIM domain-2); FHL2 interacts exclusively with the non-processed HCF-1 precursor; FHL2 and HCF-1 co-stimulate transcription of an HCF-1-dependent target gene; thus, site-specific proteolysis of HCF-1 regulates its interaction with FHL2 and modulates coactivator activity.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assay, domain analysis with processed vs. unprocessed HCF-1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing processing-state selectivity plus functional reporter assay, single lab\",\n      \"pmids\": [\"16624878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HCF-1 localizes to the Golgi apparatus in unstimulated sensory neurons; upon Golgi disruption, HCF-1 rapidly relocalizes to the nucleus, unlike other Golgi-associated proteins; this Golgi sequestration is distinct from the previously proposed ER/CREB3-mediated cytoplasmic retention, and nuclear relocalization correlates with viral reactivation.\",\n      \"method\": \"Immunofluorescence in primary neurons and latently infected mice, Golgi disruption experiments, subcellular localization studies\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in primary neurons with Golgi disruption assay, single lab\",\n      \"pmids\": [\"18667495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HCF-1 interacts directly and simultaneously with both HSV DNA replication proteins and the cellular histone chaperone Asf1b; Asf1b localizes with HCF-1 at viral replication foci; depletion of Asf1b results in significantly reduced viral DNA accumulation, establishing HCF-1 as a component of the HSV DNA replication assembly that promotes viral DNA replication by coupling Asf1b to replication components.\",\n      \"method\": \"Co-immunoprecipitation (direct and simultaneous), immunofluorescence colocalization, siRNA depletion of Asf1b with viral DNA accumulation readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct and simultaneous co-IP plus localization plus siRNA functional assay, single lab\",\n      \"pmids\": [\"20133788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of the C. elegans HCF-1 homolog (Ce HCF-1) at reduced temperatures causes embryonic lethality with mitotic and cytokinetic defects; viable mutant embryos display reduced levels of phospho-histone H3 serine 10 (H3S10P); mammalian cells with defective HCF-1 also display defects in mitotic H3S10P status, indicating a conserved role for HCF-1 in regulating mitotic histone phosphorylation.\",\n      \"method\": \"C. elegans deletion mutant analysis, immunofluorescence for H3S10P in worms and mammalian cells, tsBN67 temperature-shift experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two model systems with defined histone modification readout, single lab\",\n      \"pmids\": [\"18043729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Inactivation of pRb family members (pRb, p107, p130) by SV40 large T antigen or adenovirus E1A bypasses the requirement for HCF-1 function in tsBN67 cell proliferation and cytokinesis, without restoring HCF-1 chromatin association; this epistasis indicates that HCF-1 regulates cell proliferation and cytokinesis at least in part by opposing pRb family member function.\",\n      \"method\": \"Genetic epistasis using SV40 Tag and E1A, tsBN67 complementation assays, pRb family member mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined molecular mechanism (pRb family inactivation), single lab\",\n      \"pmids\": [\"12215534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Missense mutations in the HCFC1 Kelch domain cause X-linked cblX disorder; siRNA-mediated knockdown of HCFC1 in fibroblasts leads to coordinate downregulation of MMACHC mRNA; consensus HCFC1 binding sites were identified in the MMACHC promoter, establishing HCFC1 as a transcriptional regulator of MMACHC expression.\",\n      \"method\": \"siRNA knockdown, RT-PCR, promoter binding site analysis, patient fibroblast studies\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA functional assay plus promoter analysis in disease-relevant cells, single lab\",\n      \"pmids\": [\"24011988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Zebrafish hcfc1b regulates cranial neural crest cell differentiation and proliferation within posterior pharyngeal arches; hcfc1b-mediated craniofacial abnormalities were rescued by expression of human MMACHC, establishing that HCFC1 acts upstream of MMACHC in craniofacial development.\",\n      \"method\": \"Zebrafish morpholino knockdown, rescue by MMACHC expression, analysis of neural crest cell differentiation/proliferation\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with specific downstream rescue experiment, single lab\",\n      \"pmids\": [\"25281006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP; upon binding, HCF-1 recruits OGT to O-GlcNAcylate ChREBP and activate it; the HCF-1:ChREBP complex resides at lipogenic gene promoters where HCF-1 regulates H3K4 trimethylation and recruits the histone demethylase PHF2 for epigenetic activation of lipogenic genes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, O-GlcNAcylation assays, glucose-responsive cell culture experiments, genetic knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, ChIP, OGT-dependent modification assays, glucose-responsive experiments), mechanistically comprehensive, single lab\",\n      \"pmids\": [\"31227231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OGT-mediated glycosylation and HCF-1 proteolysis occur through separable mechanisms within the same active site; a specific TPR domain contact with HCF-1 substrate is critical for proteolysis but not Ser/Thr glycosylation; key catalytic domain residues and UDP-GlcNAc oxygen important for glycosylation are irrelevant for proteolysis; single-activity OGT enzymes (either glycosylase-only or protease-only) can be engineered in vitro and in vivo.\",\n      \"method\": \"Active-site mutagenesis, in vitro glycosylation and proteolysis assays, engineered OGT variants\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with in vitro reconstitution of both activities, mechanistically definitive, single lab\",\n      \"pmids\": [\"27056667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The HCF-1PRO repeat cleavage signal has specific OGT-binding properties; the glutamate at the cleavage site inhibits OGT:UDP-GlcNAc association; a novel OGT-binding sequence adjacent to the first HCF-1PRO repeat enhances cleavage, demonstrating that distinct OGT-binding sites in HCF-1 cooperate to promote proteolysis.\",\n      \"method\": \"In vitro OGT binding assays, mutagenesis of cleavage site glutamate, biochemical cleavage assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays with mutagenesis, single lab\",\n      \"pmids\": [\"26305326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The HCF-1PRO repeat threonine-rich region is tightly bound by the OGT TPR region and activates both OGT glycosylation and proteolysis activities; linkage of this region to heterologous sequences potentiates serine glycosylation with poor OGT co-substrates and enables proteolysis of non-HCF-1PRO cleavage sequences containing an appropriately positioned glutamate.\",\n      \"method\": \"In vitro OGT glycosylation and proteolysis assays with chimeric substrates, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with chimeric substrates and mutagenesis, single lab\",\n      \"pmids\": [\"30224358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"During the G1-to-S transition, E2F1 associates with HCF-1 through a short DHQY sequence; this HCF-1-binding sequence permits E2F1 to stimulate both DNA damage and apoptosis; HCF-1 and MLL family H3K4 methyltransferases have important functions in E2F1-mediated apoptosis; sequence changes in the E2F1 HCF-1-binding site modulate E2F1-induced apoptosis.\",\n      \"method\": \"Mutagenesis of E2F1 DHQY motif, co-immunoprecipitation, apoptosis assays, DNA damage assays, HCF-1 and MLL knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HBM mutagenesis plus co-IP plus functional apoptosis assay, single lab\",\n      \"pmids\": [\"19763085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The HCF-1 binding motif (HBM) occurs in a wide spectrum of DNA-binding proteins and cofactors; Krox20 and E2F4 show strong requirement for functional HCF-1 to activate transcription; in Krox20, the HBM lies in the N-terminal activation domain and its mutation diminishes both transactivation and association with the HCF-1 beta-propeller; the HCF-1C activation domain contributes to Krox20-mediated activation, possibly through recruitment of p300.\",\n      \"method\": \"Reporter gene assays, co-immunoprecipitation, mutagenesis of HBM in Krox20\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus mutagenesis plus functional reporter assay, single lab\",\n      \"pmids\": [\"14532282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"THAP11 physically associates with HCF-1 and recruits HCF-1 to target gene promoters in colon cancer cells; THAP11-mediated gene regulation and chromatin association require HCF-1, while HCF-1 recruitment at THAP11 target genes requires THAP11, demonstrating mutual dependence.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown of THAP11 and HCF-1, gene expression profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, ChIP, and double knockdown, single lab\",\n      \"pmids\": [\"22371484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The THAP11/ZNF143/HCFC1 complex is recruited to chromatin through the ACTACA submotif shared by THAP11 and ZNF143; its position, spacing, and orientation relative to the ZNF143 core motif are critical for THAP11 and HCFC1 recruitment to ZNF143-occupied loci; CRISPR-Cas9-mediated alteration of the ACTACA submotif at endogenous promoters reduces THAP11 and HCFC1 binding and alters target gene transcription and histone modifications.\",\n      \"method\": \"CRISPR-Cas9 mutagenesis at endogenous promoters, synthetic chromatin-integrated constructs, ChIP, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-Cas9 editing at endogenous loci plus synthetic constructs, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26416877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSP90 is required for the stability of nuclear HCFC1; HSP90 is required to maintain expression of HCFC1-targeted cell-cycle genes; HSP90 inhibition leads to HCFC1 degradation and consequent downregulation of cell-cycle gene expression.\",\n      \"method\": \"Three independent systematic analyses, biochemical co-immunoprecipitation, HSP90 inhibitor treatment, HCFC1 depletion with cell-cycle gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal approaches identifying HCFC1 as HSP90 client, functional validation of downstream gene expression, single lab\",\n      \"pmids\": [\"31693902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HCF-1 conditional knockout in mouse hepatocytes demonstrates that HCF-1 is required for cell-cycle re-entry and proliferation in resting adult liver cells; HCF-1-deficient hepatocytes fail to re-enter the cell cycle during liver regeneration; in embryos, epiblast-specific HCF-1 loss causes cell-cycle exit and apoptosis of HCF-1-negative cells by E8.5.\",\n      \"method\": \"Cre-inducible conditional knockout mouse model, liver regeneration model, BrdU incorporation, apoptosis assays, X-chromosome inactivation analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout in two physiological contexts (embryo and adult liver regeneration), defined cellular and molecular phenotypes\",\n      \"pmids\": [\"26921005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Complete epiblast-specific loss of HCF-1 in male embryos leads to developmental arrest at E6.5 with rapid progressive cell-cycle exit, failure of anterior visceral endoderm migration, failure of primitive streak formation, and absence of gastrulation; the pattern of lethality resembles loss of β-catenin function.\",\n      \"method\": \"Conditional knockout mouse model (Hcfc1 epiKO/Y), developmental staging, immunohistochemistry, cell-cycle analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with staged developmental analysis and defined molecular markers, single lab\",\n      \"pmids\": [\"27521049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SETD5 regulates RNA polymerase II promoter-proximal pausing on E2F target genes in hematopoietic stem cells in cooperation with HCF-1 and the PAF1 complex; loss of Setd5 disrupts HSC quiescence; HCF-1 co-immunoprecipitates with SETD5.\",\n      \"method\": \"Co-immunoprecipitation of SETD5 and HCF-1, conditional knockout mouse model, Pol II ChIP, transcriptome analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus in vivo KO, single lab; HCF-1 role is partly inferred from the co-IP and shared target gene regulation\",\n      \"pmids\": [\"34853439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HCF-1 activates CDC42 expression by binding to the -881 to -575 region upstream of the CDC42 transcription start site; overexpression of constitutively active CDC42F28L rescues G1 phase delay and multinucleate defects caused by HCF-1 loss, establishing CDC42 as a functional downstream target of HCF-1 in cell cycle progression.\",\n      \"method\": \"ChIP to the CDC42 promoter, siRNA depletion of HCF-1, rescue by constitutively active CDC42, cell cycle and multinucleation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific promoter region plus functional rescue experiment, single lab\",\n      \"pmids\": [\"33097698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HCF-1 is required for INS-1 pancreatic β-cell glucose-stimulated insulin secretion; HCF-1 reduction causes decreased expression of Pdx1; HCF-1 and E2F1 co-localize at the Pdx1 promoter as shown by ChIP.\",\n      \"method\": \"siRNA knockdown, glucose-stimulated insulin secretion assay, RT-PCR for Pdx1, ChIP\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at Pdx1 promoter plus functional insulin secretion assay, single lab\",\n      \"pmids\": [\"24250814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, HCF-1 chromatin localization is largely dependent on functional SET-26; SET-26 and HCF-1 cooperate to regulate a common set of target genes; the histone deacetylase HDA-1 opposes both SET-26 and HCF-1 at a subset of shared target genes and in longevity regulation.\",\n      \"method\": \"ChIP, genetic epistasis (set-26, hcf-1, hda-1 mutants), gene expression profiling, lifespan assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic epistasis with transcriptomic validation, single lab\",\n      \"pmids\": [\"38485937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mouse models of Hcfc1 mutation exhibit reduced expression of MMACHC (confirming transcriptional regulation) and additionally show reduced expression of ribosomal protein subunit genes; developmental defects associated with these mutations include aspects of both cblC and ribosomopathies, identifying HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development.\",\n      \"method\": \"Mouse conditional knockout models, RNA-seq, metabolic analysis, developmental phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models with transcriptomic profiling, single lab\",\n      \"pmids\": [\"35013307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of HCF-1 in sensory neurons in vivo causes a striking reduction in latently infected neurons that initiate HSV-1 reactivation; this correlated with a defect in removal of repressive heterochromatin from latent viral genomes, establishing HCF-1 as a critical in vivo regulator that promotes the transition of latent HSV genomes from a repressed chromatin state.\",\n      \"method\": \"HCF-1 conditional knockout mouse model, HSV latency/reactivation model, ChIP for repressive chromatin marks, viral reactivation quantification\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with ChIP chromatin analysis and viral reactivation readout, single lab but first in vivo demonstration\",\n      \"pmids\": [\"36692302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hepatocyte-specific HCF-1 deletion leads to progressive loss of OGT protein levels and global O-GlcNAcylation without altering OGT mRNA, indicating post-translational regulation of OGT stability by HCF-1; loss of HCF-1 reduces nuclear OGT and O-GlcNAcylation, mimicking fasting conditions; HCF-1-negative hepatocytes display cytoplasmic O-GlcNAcylation while HCF-1-positive cells maintain nuclear localization.\",\n      \"method\": \"Hepatocyte-specific conditional knockout mouse, immunofluorescence, Western blot, OGT mRNA analysis, fractionation studies\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with multi-method validation of OGT stability and localization, single lab\",\n      \"pmids\": [\"40754593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HCF-1 is required for neuronal differentiation and forebrain commissure formation; HCF-1 directly occupies promoters of key neuronal genes (Elavl3, NeuroD1) and its loss reduces activating chromatin marks at these loci; OGT inhibition phenocopies HCF-1 depletion in impairing neuronal proliferation, differentiation, and neurite outgrowth; glycoproteomic analysis reveals disruption of OGT-dependent protein networks involved in neuronal structure.\",\n      \"method\": \"Conditional neuronal knockout, ChIP at neuronal gene promoters, siRNA depletion, OGT inhibitor (OSMI-1), glycoproteomics, transcriptomics\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO plus ChIP plus OGT inhibitor phenocopy, single lab\",\n      \"pmids\": [\"41651253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HCF-1 binds to the C-terminal ~200 amino acids of ASXL1 and promotes ASXL1 proteasome-dependent turnover; deletion of this ASXL1 C-terminal region abrogates HCF-1 binding and stabilizes ASXL1; HCF-1 and BAP1 show reciprocal antagonism in association with ASXL1, suggesting indirect coupling in complex assembly.\",\n      \"method\": \"P2A dual-reporter stability assay, co-immunoprecipitation, proteasome inhibitor experiments, domain deletion mapping\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping plus functional stability assay plus BAP1 competition, single lab\",\n      \"pmids\": [\"41968849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM2A recruits E2F1 and HCFC1 to promoters of key meiosis genes (Stra8, Meiosin, Spo11, Sycp1) in male germ cells; conditional deletion of Kdm2a disrupts H3K36me2/3 deposition and impairs expression of HCFC1-recruited target genes required for meiotic entry and progression.\",\n      \"method\": \"Co-immunoprecipitation of KDM2A-E2F1-HCFC1, ChIP at meiotic gene promoters, conditional knockout mouse, H3K36me2/3 analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus in vivo KO, single lab; HCFC1 role shown as part of KDM2A complex\",\n      \"pmids\": [\"39160277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A second HCF-like protein HCF-2 was identified; chimeric protein analysis showed that differences between the fifth and sixth kelch repeats of the beta-propeller domains of HCF-1 and HCF-2 determine selective recruitment of HCF-1 over HCF-2 by VP16 and LZIP.\",\n      \"method\": \"Chimeric protein construction, in vitro binding assays, VP16-induced complex assembly assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric protein domain swapping with functional complex assembly assays, single lab\",\n      \"pmids\": [\"10196288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RONIN (THAP11) modulates TFEB transcriptional activity through its interaction with HCF-1/HCFC1; RONIN overexpression improved autophagy levels, lysosomal activity, and attenuated D-galactose-induced hair cell senescence, working through TFEB activation.\",\n      \"method\": \"Co-immunoprecipitation of RONIN and HCF1, overexpression studies, autophagy/lysosomal activity assays, hair cell senescence model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional overexpression with autophagy readout, single lab\",\n      \"pmids\": [\"39985193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HSP90 N-terminal inhibition reduces HCFC1 protein levels, preventing HCFC1 from binding to the TFEB proximal promoter; decreased TFEB transcription then reduces LC3 levels and promotes mitochondria-derived vesicle (MDV) formation and tumor metastasis; re-activation of the HCFC1-TFEB-LC3 axis by blocking MDV formation suppresses metastasis.\",\n      \"method\": \"ChIP for HCFC1 at TFEB promoter, HSP90 inhibitor treatment, HSP90AA1-HCFC1 co-immunoprecipitation, TFEB/LC3 Western blot, MDV formation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at TFEB promoter plus co-IP plus functional metabolic assays, single lab\",\n      \"pmids\": [\"39461872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HCFC1 (HCF-1) is a metazoan transcriptional co-regulator that undergoes OGT-catalyzed proteolytic maturation at centrally located HCF-1PRO repeats (occurring within the OGT glycosyltransferase active site via a glutamate cleavage mechanism), generating stably associated HCF-1N and HCF-1C subunits that control distinct cell-cycle phases: HCF-1N promotes G1/S progression by associating with E2F1, THAP11, ZNF143, and other sequence-specific factors to recruit MLL/Set1 H3K4 methyltransferases and Sin3 HDAC to target promoters, while HCF-1C ensures proper M-phase exit and cytokinesis by regulating PR-Set7 and H4-K20 methylation status; additionally, HCF-1 is O-GlcNAcylated by OGT in a nutrient-responsive manner that gates its interaction with ChREBP to epigenetically activate lipogenic genes, it is stabilized by HSP90 in the nucleus, its subcellular localization is regulated (Golgi sequestration in neurons, CRM1-dependent cytoplasmic export via HPIP) to gate herpesvirus reactivation, and BAP1 deubiquitinates HCF-1N Lys-48 polyubiquitin chains to modulate HCF-1-dependent proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HCFC1 (HCF-1) is a chromatin-associated transcriptional co-regulator that couples sequence-specific DNA-binding factors to histone-modifying machinery to control cell proliferation, cell-cycle progression, and developmental gene programs [#0, #4]. It is synthesized as a precursor that undergoes site-specific proteolytic maturation by O-GlcNAc transferase (OGT) at centrally located HCF-1PRO repeats, generating an HCF-1N and an HCF-1C subunit that remain associated through interdigitated fibronectin type-3 (SAS1/SAS2) elements and a C-terminal nuclear localization signal [#2, #8, #9]. Structural and biochemical work established that OGT engages the HCF-1PRO repeat via its TPR domain, positions the cleavage region in the glycosyltransferase active site, and cleaves between cysteine and glutamate to yield a pyroglutamate product, with glycosylation and proteolysis being mechanistically separable activities of the same active site [#3, #27]. The two subunits perform distinct cell-cycle roles: HCF-1N promotes G1/S progression, recruiting MLL/Set1 H3K4 methyltransferases and the Sin3 HDAC complex to target promoters together with sequence-specific factors such as E2F1, while HCF-1C ensures proper mitotic exit and cytokinesis, in part by regulating the H4-K20 methyltransferase PR-Set7 and mitotic histone modification status [#0, #4, #5, #6]. HCF-1 is targeted to thousands of active promoters by a small set of partner factors — notably THAP11, ZNF143, and E2F family proteins binding via an HCF-1 binding motif (HBM) and shared submotifs — to direct transcription of cell-cycle, biosynthetic, and metabolic genes [#13, #14, #33], including direct activation of CDC42 [#38]. Its activity is gated by post-translational and metabolic inputs: glucose-stimulated O-GlcNAcylation licenses binding to ChREBP for epigenetic activation of lipogenic genes [#26], HSP90 maintains nuclear HCF-1 stability and expression of its cell-cycle target genes [#34], and BAP1 deubiquitinates Lys-48 chains on the HCF-1N Kelch domain to modulate proliferation [#7]. In vivo, HCF-1 is required for cell-cycle re-entry and proliferation in regenerating liver and for epiblast survival and gastrulation [#35, #36], and it promotes herpesvirus reactivation by driving removal of repressive heterochromatin from latent viral genomes [#42]. Missense mutations in the HCFC1 Kelch domain cause X-linked cblX disorder, linked to loss of HCFC1-driven MMACHC transcription [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the structural logic of subunit association, answering how the two HCF-1 fragments remain a functional unit after processing.\",\n      \"evidence\": \"Domain deletion, co-IP, and nuclear localization assays defining SAS1/SAS2 and the C-terminal NLS\",\n      \"pmids\": [\"10958670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how processing is triggered\", \"Atomic structure of the interface not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that HCF-1 chromatin association through its Kelch/beta-propeller domain is required for proliferation, linking a binding activity to a proliferative function.\",\n      \"evidence\": \"Chromatin fractionation and temperature-shift in tsBN67 cells\",\n      \"pmids\": [\"11340173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the chromatin-tethering partner factors\", \"Mechanism connecting chromatin loss to arrest unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected HCF-1 to multiple regulatory contexts — spliceosomal snRNPs, a C-terminal activation domain augmented by p300, the pRb pathway, and HPIP-mediated CRM1 export — broadening its functional reach beyond a single coactivator role.\",\n      \"evidence\": \"Co-IP, in vitro splicing, reporter assays, genetic epistasis, and CRM1-inhibition localization studies\",\n      \"pmids\": [\"12456665\", \"12271126\", \"12215534\", \"12235138\", \"12149646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing role not integrated with transcriptional functions\", \"Physiological significance of cytoplasmic export incompletely defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the two-subunit, two-cell-cycle-stage model and the histone-modifier tethering function, establishing HCF-1 as a bifunctional cell-cycle regulator.\",\n      \"evidence\": \"siRNA depletion across cell lines with cell-cycle/cytokinesis readouts, co-IP and domain mapping of Sin3 and Set1/Ash2 complexes, and HBM analysis across DNA-binding proteins\",\n      \"pmids\": [\"12743030\", \"12670868\", \"14532282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how proteolysis separates the two functions mechanistically\", \"Promoter-level target genes not yet genome-wide\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified PR-Set7/H4-K20 methylation control as the molecular basis of HCF-1C mitotic function, linking the C-subunit to chromosome segregation.\",\n      \"evidence\": \"siRNA depletion, histone modification Westerns, and PR-Set7 overexpression rescue\",\n      \"pmids\": [\"15200950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which HCF-1C controls PR-Set7 expression unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped HCF-1's G1/S coactivator mechanism onto E2F factors and conserved mitotic H3S10 phosphorylation control, defining its proliferative gene-activation route.\",\n      \"evidence\": \"Co-IP, ChIP at E2F promoters, cell-cycle staging, and C. elegans/mammalian H3S10P analysis\",\n      \"pmids\": [\"17612494\", \"18043729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HCF-1 switches between E2F activator and repressor complexes not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a conserved repressive role for HCF-1 on FOXO/DAF-16 signaling and lifespan, extending its function to stress and longevity regulation.\",\n      \"evidence\": \"C. elegans co-IP, ChIP, genetic epistasis, and lifespan assays; extended with SIR-2.1 epistasis and conservation in mammals\",\n      \"pmids\": [\"18828672\", \"21909281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin mechanism of DAF-16 repression not fully resolved\", \"Mammalian longevity relevance only inferred from target-gene overlap\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established HCF-1's promoter-targeting partners (THAP1, THAP11/Ronin) and its direct participation in HSV DNA replication and Golgi-gated localization, integrating recruitment and viral life-cycle control.\",\n      \"evidence\": \"Proteomics, in vitro binding, co-IP, ChIP, ChIP-seq in ESCs, immunofluorescence in neurons, and Asf1b depletion with viral DNA readouts\",\n      \"pmids\": [\"20200153\", \"20581084\", \"20133788\", \"18667495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering Golgi-to-nucleus relocalization undefined\", \"How a single factor coordinates host transcription and viral replication unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved that OGT is the protease that cleaves HCF-1 and that cleavage per se, not merely fragment separation, is required for HCF-1C function, unifying glycosylation and maturation under one enzyme.\",\n      \"evidence\": \"In vitro OGT cleavage assays, HCF-1PRO mutagenesis, and cell-based M-phase assays\",\n      \"pmids\": [\"21295698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cleavage not yet determined at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural and genome-wide mechanism: how OGT positions and cleaves the PRO repeat, and how a few sequence-specific factors direct HCFC1 to thousands of active promoters, plus the disease link to cblX.\",\n      \"evidence\": \"Crystal structure of OGT:HCF-1PRO complex with active-site mutagenesis; ChIP-seq with motif/co-localization analysis; patient mutation and MMACHC promoter studies\",\n      \"pmids\": [\"24311690\", \"23539139\", \"24011988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all co-localizing factors bind HCFC1 directly not validated\", \"How cblX mutations alter chromatin engagement not structurally resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated in vivo requirement for HCF-1 in proliferation and development and dissected OGT's dual glycosylation/proteolysis activities into separable mechanisms.\",\n      \"evidence\": \"Conditional knockout in mouse hepatocytes/epiblast; active-site mutagenesis and engineered single-activity OGT variants\",\n      \"pmids\": [\"26921005\", \"27521049\", \"27056667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving embryonic/regenerative phenotypes not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked HCF-1 to nutrient-responsive metabolic transcription and to HSP90-dependent stability, showing how its activity and abundance are gated by upstream signals.\",\n      \"evidence\": \"Glucose-responsive co-IP/ChIP/O-GlcNAc assays for ChREBP; HSP90 inhibition with HCFC1 degradation and cell-cycle gene readouts\",\n      \"pmids\": [\"31227231\", \"31693902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether metabolic and cell-cycle programs are regulated by the same HCF-1 pool unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the promoter-recruitment and tissue-specific roles of HCF-1 to ribosome biogenesis, meiotic entry, neuronal differentiation, and OGT stability, defining context-specific gene programs.\",\n      \"evidence\": \"Mouse conditional knockouts with RNA-seq, ChIP at meiotic/neuronal/MMACHC/ribosomal loci, KDM2A and SET-26 co-IP/epistasis, and OGT inhibitor phenocopy\",\n      \"pmids\": [\"35013307\", \"39160277\", \"41651253\", \"40754593\", \"38485937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these tissue programs share a common HCF-1 mechanism unresolved\", \"Direct vs complex-mediated recruitment in several contexts inferred from co-IP\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected HCF-1 to autophagy/lysosomal control via TFEB transcription and to protein-stability regulation of ASXL1, broadening its regulatory outputs.\",\n      \"evidence\": \"Co-IP and overexpression with autophagy/lysosomal and senescence readouts; ChIP at TFEB promoter; stability/co-IP assays for ASXL1 with BAP1 competition\",\n      \"pmids\": [\"39985193\", \"39461872\", \"41968849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TFEB axis mostly shown via overexpression/inhibitor perturbation\", \"Functional consequence of HCF-1-driven ASXL1 turnover in vivo undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HCF-1 selects among its many partner factors and chromatin-modifier complexes to execute distinct programs (G1/S vs mitosis, proliferation vs lipogenesis vs autophagy) in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of partner-selection logic\", \"Quantitative contribution of OGT-cleavage, O-GlcNAcylation, HSP90, and BAP1 to context-specific outputs not integrated\", \"Structural basis of full HCF-1N:HCF-1C:partner assemblies on chromatin lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 6, 26, 38]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [24, 38, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 45]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 34]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 14, 42]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 6, 35]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 13, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 26, 33]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [35, 36, 25, 44]}\n    ],\n    \"complexes\": [\n      \"Set1/Ash2 H3K4 methyltransferase complex\",\n      \"Sin3 HDAC complex\",\n      \"THAP11/ZNF143/HCFC1 complex\"\n    ],\n    \"partners\": [\n      \"OGT\",\n      \"THAP11\",\n      \"ZNF143\",\n      \"E2F1\",\n      \"BAP1\",\n      \"HSP90\",\n      \"ChREBP\",\n      \"ASXL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}