{"gene":"PCGF2","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1995,"finding":"MEL-18 (PCGF2) acts as a sequence-specific transcriptional repressor via direct binding to the DNA sequence 5'-GACTNGACT-3', found in regulatory regions of c-myc, bcl-2, and Hox genes.","method":"In vitro DNA binding assays and transcriptional reporter assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA binding demonstrated with functional transcriptional repression, single lab but two orthogonal methods","pmids":["8521824"],"is_preprint":false},{"year":1993,"finding":"The MEL-18 (PCGF2) protein contains a RING-finger motif, a helix-loop-helix (HLH)-like structure, and a Pro/Ser-rich region, and the protein localizes to the nucleus. The human gene maps to chromosome 12q22.","method":"cDNA cloning, sequence analysis, in situ hybridization","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and structural characterization with chromosomal mapping by two orthogonal methods","pmids":["8325509"],"is_preprint":false},{"year":1996,"finding":"Mel-18 knockout mice display posterior homeotic transformations of the axial skeleton with ectopic expression of Hox cluster genes, establishing Mel-18 (PCGF2) as a Polycomb group gene required to maintain Hox gene silencing in paraxial mesoderm.","method":"Homologous recombination knockout mice, skeletal analysis, in situ hybridization for Hox gene expression","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined molecular phenotype (ectopic Hox expression), replicated across multiple mutant animals","pmids":["8625838"],"is_preprint":false},{"year":1997,"finding":"Mel-18 (PCGF2) loss-of-function results in severe combined immunodeficiency due to impaired mitotic response of lymphocyte precursors to IL-7 stimulation; the identical phenotype in mel-18 and bmi-1 mutants places them in the same genetic cascade controlling cell cycle progression in the immune system.","method":"Knockout mice, lymphocyte proliferation assays, genetic epistasis (mel-18 vs bmi-1 mutant comparison)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular phenotype and genetic epistasis analysis across two independent mutants","pmids":["9252126"],"is_preprint":false},{"year":1998,"finding":"Mel-18 (PCGF2) negatively regulates cell cycle progression via a c-Myc/CDC25 cascade; overexpression arrests B cells at G1 with downregulation of c-Myc, cyclins D2/E, and CDKs, and this arrest is rescued in mel-18/c-myc double-transgenic mice, placing c-Myc downstream of Mel-18.","method":"Transgenic mice, double-transgenic epistasis, Western blotting, CDK activity assays, flow cytometry","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double-transgenic rescue, multiple biochemical readouts in a single rigorous study","pmids":["9806630"],"is_preprint":false},{"year":2001,"finding":"Mel-18 (PCGF2) is required for Th2 cell differentiation; mel-18 knockout T cells show defective IL-4 gene demethylation and reduced GATA3 induction, placing Mel-18 upstream of epigenetic remodeling at the IL-4 locus during Th2 polarization.","method":"Knockout mice, cytokine production assays, DNA methylation analysis, GATA3 expression analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple orthogonal mechanistic readouts (DNA methylation, transcription factor expression, cytokine production)","pmids":["11520462"],"is_preprint":false},{"year":2003,"finding":"Mel-18 (PCGF2) forms homodimers requiring the N-terminal RING-finger and alpha-helix domains; homodimerization is regulated by phosphorylation state, with dephosphorylated Mel-18 able to homodimerize, and this is controlled by PKC and phosphatases.","method":"In vitro pull-down assays, co-immunoprecipitation in transfected COS-7 cells, deletion analysis, PKC inhibitor/phosphatase experiments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vitro and in vivo pulldowns with deletion mapping and pharmacological modulation, single lab","pmids":["12480532"],"is_preprint":false},{"year":2004,"finding":"Mel-18 (PCGF2) negatively regulates hematopoietic stem cell self-renewal; mel-18 knockout HSCs show elevated Hoxb4 expression, increased G0 phase proportion, and enhanced long-term reconstitution activity, while mel-18 transgenic mice show the opposite.","method":"Knockout and transgenic mice, competitive repopulation assays, quantitative RT-PCR for Hoxb4, cell cycle analysis","journal":"Experimental hematology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with defined molecular target (Hoxb4) and functional in vivo readout","pmids":["15183898"],"is_preprint":false},{"year":2005,"finding":"Mel-18 (PCGF2) supports early T progenitor expansion by maintaining Hes-1 expression, a Notch pathway target; mel-18 knockout early T progenitors fail to maintain Notch-induced Hes-1 expression, placing Mel-18 as a required epigenetic memory component for Notch-driven transcription.","method":"Knockout mice, in vivo and in vitro T progenitor assays, quantitative RT-PCR for Hes-1, Delta-like-1 co-culture","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with mechanistic target (Hes-1) identified, single lab with two experimental systems (in vivo and in vitro)","pmids":["15728456"],"is_preprint":false},{"year":2005,"finding":"Mel-18 (PCGF2) directly interacts with cyclin D2 via its C-terminal proline/serine-rich domain (P/S domain), and Mel-18 inhibits cyclin D2 activity; knockdown of Mel-18 in cyclin D2-overexpressing cells increases proliferative activity.","method":"Yeast two-hybrid screen, co-localization studies, deletion mapping, antisense knockdown with proliferation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-localization plus functional knockdown, single lab, binding domain mapped","pmids":["16182291"],"is_preprint":false},{"year":2005,"finding":"MEL-18 (PCGF2) was identified as a novel lamin A/C-interacting protein by yeast two-hybrid; co-immunoprecipitation of endogenous proteins did not show differential binding between normal and progerin (HGPS mutant lamin A), indicating no unique interaction with progerin.","method":"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid identification with endogenous co-IP showing no differential binding; interaction confirmed but context is non-specific","pmids":["16248985"],"is_preprint":false},{"year":2006,"finding":"Mel-18 (PCGF2) transcriptionally represses Bmi-1 expression, and this repression of Bmi-1 by Mel-18 mediates accelerated cellular senescence and shortening of replicative lifespan; Mel-18 also down-regulates c-Myc, which in turn controls Bmi-1 expression.","method":"Promoter-reporter assays, chromatin immunoprecipitation, quantitative RT-PCR, RNA interference, overexpression in human fibroblasts","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, promoter reporter, ChIP, RNAi) in a single rigorous study establishing direct transcriptional regulation","pmids":["17151361"],"is_preprint":false},{"year":2007,"finding":"MEL-18 (PCGF2) forms a PRC1-like complex (melPRC1) containing RING1/2, HPH2, and CBX8; a reconstituted Ring1B/Mel-18 subcomplex functions as an E3 ubiquitin ligase that ubiquitylates histone H2A specifically at lysine 119 in nucleosomes, with Ring1B providing E3 catalytic activity and Mel-18 directing specificity to H2AK119 in chromatin. This substrate-targeting function requires prior phosphorylation of Mel-18 at multiple residues.","method":"Affinity purification/mass spectrometry, in vitro reconstitution of E3 ligase activity, nucleosome ubiquitylation assay, mutational analysis, phosphorylation mapping","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of E3 ligase with nucleosome substrates, mutagenesis, phosphorylation analysis, multiple orthogonal methods in a single rigorous study","pmids":["17936708"],"is_preprint":false},{"year":2007,"finding":"Mel-18 (PCGF2) represses Bmi-1 expression and consequently down-regulates Akt/PKB activity in breast cancer cells; constitutively active Akt overrides the tumor-suppressive effect of Mel-18, placing Akt downstream of the Mel-18→Bmi-1 axis.","method":"Overexpression, RNA interference knockdown, Akt kinase activity assays, constitutively active Akt rescue experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue with constitutively active Akt, RNAi and overexpression, single lab","pmids":["17545584"],"is_preprint":false},{"year":2007,"finding":"Bmi-1 and Mel-18 (PCGF2) form complexes with overlapping protein compositions in cancer cells, and their knockdown produces similar effects on medulloblastoma cell proliferation and tumor formation, suggesting shared functional roles in cancer cell growth.","method":"Proteomics-based complex characterization, shRNA knockdown, clonogenic survival, anchorage-independent growth, xenograft tumor formation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-based complex characterization plus functional knockdown with in vivo readout, single lab","pmids":["17452456"],"is_preprint":false},{"year":2008,"finding":"MEL-18 (PCGF2) interacts with HSF2 and inhibits HSF2 sumoylation by binding to and inhibiting the SUMO E2 enzyme UBC9; MEL-18 overexpression decreases and RNAi-mediated knockdown increases HSF2 sumoylation. The MEL-18/HSF2 interaction decreases during mitosis, explaining elevated mitotic HSF2 sumoylation.","method":"Co-immunoprecipitation, overexpression, RNA interference, in vitro sumoylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, gain- and loss-of-function with biochemical readout, in vitro activity assay, single lab with multiple orthogonal methods","pmids":["18211895"],"is_preprint":false},{"year":2008,"finding":"MEL-18 (PCGF2) interacts with RanGAP1 and inhibits its sumoylation independently of the Mel-18 RING domain; RanGAP1 sumoylation decreases during mitosis concomitant with increased MEL-18/RanGAP1 interaction.","method":"Co-immunoprecipitation, sumoylation assays, cell cycle fractionation, domain deletion analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional sumoylation assay and domain mapping, single lab","pmids":["18706886"],"is_preprint":false},{"year":2008,"finding":"Mel-18 (PCGF2) negatively regulates cell cycle G1-S progression in breast cancer through the PI3K/Akt pathway via cyclin D1 down-regulation and p27(Kip1) phosphorylation at Thr157, independent of INK4a/ARF genes; Mel-18 reduces Akt phosphorylation at Ser473, inhibits GSK-3β phosphorylation, reduces β-catenin nuclear localization, and lowers TCF/LEF promoter activity.","method":"Overexpression, antisense knockdown, flow cytometry, CDK activity assays, Western blotting, luciferase reporter assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with multiple pathway readouts, single lab","pmids":["18519679"],"is_preprint":false},{"year":2011,"finding":"PCGF2 (Mel-18) binds directly to HOXA7 chromatin and represses HOXA7 expression, acting upstream of HOXA7 in PRC1-mediated suppression of granulocytic differentiation in HL-60 cells; PCGF2 silencing de-represses HOXA7 and is sufficient to induce granulocytic differentiation.","method":"shRNA knockdown, chromatin immunoprecipitation (ChIP), differentiation marker assays, NBT staining, cell cycle analysis, overexpression of HOXA7","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct chromatin binding plus functional epistasis analysis, single lab","pmids":["22085718"],"is_preprint":false},{"year":2011,"finding":"Mel-18 (PCGF2) negatively regulates HIF-1α protein level and VEGF transcription via the PTEN/PI3K/Akt/MDM2 pathway; Mel-18 loss downregulates PTEN, activates PI3K/Akt/MDM2, increases HIF-1α, and retains FOXO3a in the cytoplasm, promoting HIF-1α/CBP complex recruitment to the VEGF promoter and tumor angiogenesis.","method":"Knockdown, overexpression, Western blotting, luciferase reporter assays, tube formation assays, in vivo xenograft experiments with microvessel density quantification","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway components tested with in vitro and in vivo readouts, single lab","pmids":["21602890"],"is_preprint":false},{"year":2011,"finding":"Mel-18 (PCGF2) binding at the Il17a promoter positively regulates IL-17a and IL-17f expression in Th17 cells; Mel-18 binding is inducible, dependent on TCR signaling, requires continuous TGF-β for maintenance, and correlates with RORγt recruitment to the Il17a promoter.","method":"Chromatin immunoprecipitation (ChIP), RNAi knockdown, cytokine expression assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding correlated with RORγt recruitment, RNAi validation, single lab","pmids":["21674483"],"is_preprint":false},{"year":2012,"finding":"Mel-18 (PCGF2) loss activates Wnt/TCF-mediated upregulation of Jagged-1 (a Notch ligand) and consequently activates Notch signaling to expand breast cancer stem cells; Mel-18 knockdown enriches CD44+/CD24−/ESA+ CSC populations and increases self-renewal, while pharmacologic inhibition of Notch or Wnt abrogates these effects.","method":"shRNA knockdown, overexpression, side population assay, tumorsphere formation, in vivo tumor-initiating assay, pharmacologic pathway inhibition","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis with in vitro and in vivo readouts, single lab","pmids":["22954590"],"is_preprint":false},{"year":2013,"finding":"Mel-18 (PCGF2) epigenetically regulates miR-205 transcription by inhibiting DNMT-mediated DNA methylation of the miR-205 promoter; Mel-18 loss promotes DNA methylation at this locus, reducing miR-205, which de-represses ZEB1 and ZEB2, promoting EMT and reducing E-cadherin expression in breast cancer cells.","method":"miRNA microarray, ChIP, DNA methylation analysis (bisulfite/DNMT inhibition), overexpression, knockdown, xenograft experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, DNA methylation analysis, microRNA functional assays, in vivo), single lab","pmids":["23474752"],"is_preprint":false},{"year":2015,"finding":"MEL-18 (PCGF2) suppresses SUMOylation of ESR1 transactivators p53 and SP1, driving ESR1 transcription; MEL-18 facilitates deSUMOylation by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SENP1 (a SUMO protease). Loss of MEL-18 leads to ER-α downregulation and estrogen-independent breast cancer growth.","method":"Overexpression, knockdown, SUMOylation assays, ubiquitination assays, promoter reporter assays, in vivo xenograft experiments","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical pathway dissection with multiple orthogonal methods and in vivo validation, single lab","pmids":["25822021"],"is_preprint":false},{"year":2016,"finding":"PCGF2 (Mel-18) directly interacts with UBE2I (the SUMO E2) and inhibits UBE2I-mediated sumoylation of PML-RARA; PCGF2 knockdown alone is sufficient to induce sumoylation-, ubiquitylation- and PML-NB-mediated degradation of PML-RARA, and ATO treatment disrupts the PCGF2-UBE2I interaction, allowing UBE2I to access PML-RARA.","method":"Co-immunoprecipitation, immunofluorescence, overexpression, knockdown, sumoylation assays, ubiquitylation assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP confirmed with functional sumoylation and ubiquitylation assays, single lab","pmids":["27030546"],"is_preprint":false},{"year":2018,"finding":"Missense mutations at Pro65 of PCGF2 cause a developmental syndrome (Turnpenny-Fry syndrome); computational structural modeling suggests the Pro65 substitutions alter an N-terminal loop critical for histone binding, potentially exerting dominant-negative effects by sequestering PRC1 components into complexes that cannot efficiently interact with histones.","method":"Clinical genetics (de novo missense mutations in 13 patients), computer structural modeling","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — structural mechanism is computational prediction only; human genetics establishes disease association but molecular mechanism is modeled not experimentally confirmed","pmids":["30343942"],"is_preprint":false},{"year":2019,"finding":"MEL-18 (PCGF2) epigenetically silences ADAM10/17 expression in cooperation with PRC1 and PRC2; MEL-18 loss de-represses ADAM10/17, increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization, thereby causing trastuzumab resistance in HER2+ breast cancer cells.","method":"Gene expression microarray, RTK array, shRNA knockdown, overexpression, in vivo xenograft experiments, FISH for MEL-18 amplification, pharmacologic ADAM inhibitor combination experiments","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic silencing mechanism with in vitro and in vivo rescue by pharmacologic inhibition, single lab with multiple orthogonal methods","pmids":["30265336"],"is_preprint":false},{"year":2022,"finding":"PCGF2 is required in granulosa cells for folliculogenesis and ovulation; PCGF2 binds the progesterone receptor (Pgr) promoter and upregulates Pgr expression by modifying H2AK119ub1 following hCG stimulation, and GC-specific Pcgf2 knockout mice show follicle loss, ovulation defects, and subfertility.","method":"Conditional knockout mice, ChIP for PCGF2 promoter binding, H2AK119ub1 chromatin immunoprecipitation, qRT-PCR for Pgr and downstream targets, histological analysis","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined molecular target (Pgr), ChIP demonstrating direct promoter binding and histone modification, in vivo phenotype","pmids":["36407101"],"is_preprint":false},{"year":2024,"finding":"The canonical Pcgf2-containing PRC1 complex (cPRC1.2) forms chromatin loops at bivalent promoters in mouse ESCs; loss of Pcgf2 disrupts these loops without affecting global H2AK119ub1 levels and impairs transcriptional induction of neuronal differentiation genes; CTCF is enriched at cPRC1.2 loop anchors, and neuronal differentiation involves a transition from cPRC1.2-mediated to CTCF-mediated active loops.","method":"CRISPR/Cas9 knockout in mouse ESCs, Hi-C chromatin conformation analysis, virtual 4C, ChIP-seq for H2AK119ub1 and CTCF, RNA-seq, neuronal differentiation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomic methods in a clean genetic system; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.11.13.623456"],"is_preprint":true},{"year":2024,"finding":"Canonical PRC1 containing Pcgf2/4 (cPRC1.2/1.4) plays a dominant role over non-canonical PRC1 (Pcgf3/5) in regulating neural stem cell (NSC) proliferation and lineage fate; Pcgf2/4 deletion leads to strong reduction in NSC proliferation and altered neurogenic and gliogenic fate, with stem cell and neurogenic factor genes directly bound by PRC1 and differentially expressed upon deletion.","method":"CRISPR/Cas9 deletion in NSCs, side-by-side comparison of Pcgf2/4 vs Pcgf3/5 knockouts, RNA-seq, PRC1 ChIP-seq, proliferation and differentiation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic comparison with molecular target identification by ChIP-seq, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.08.07.606990"],"is_preprint":true}],"current_model":"PCGF2 (MEL-18) is a Polycomb group RING-finger protein that functions as a core component of canonical PRC1 complexes, where it directs the Ring1B E3 ubiquitin ligase activity specifically to H2AK119 in chromatin (requiring Mel-18 phosphorylation), represses Hox and other target genes to control axial patterning and cell fate, forms chromatin loops at bivalent promoters to maintain genes poised for activation, acts as a sequence-specific transcriptional repressor (binding 5'-GACTNGACT-3'), negatively regulates cell cycle progression through a c-Myc/CDC25 cascade and via Akt/cyclin D1/p27 signaling, inhibits SUMO conjugation by sequestering the E2 enzyme UBC9 to block sumoylation of HSF2, RanGAP1, and PML-RARA, and suppresses Bmi-1 transcription (partly via c-Myc downregulation) to function as a tumor suppressor in multiple cancer types."},"narrative":{"mechanistic_narrative":"PCGF2 (MEL-18) is a Polycomb group RING-finger protein that operates as a core subunit of canonical PRC1 to enforce chromatin-based transcriptional silencing controlling axial patterning, cell-fate decisions, and proliferation [PMID:8625838, PMID:17936708]. Within a melPRC1 complex containing RING1/2, HPH2, and CBX8, PCGF2 directs the Ring1B E3 ubiquitin ligase to monoubiquitylate nucleosomal histone H2A specifically at lysine 119, a substrate-targeting function requiring prior phosphorylation of PCGF2 [PMID:17936708]; this PRC1 activity loops bivalent promoters and represses target genes including the Hox cluster, with genetic loss causing posterior homeotic transformation and ectopic Hox expression [PMID:8625838, PMID:bio_10.1101_2024.11.13.623456]. PCGF2 also acts as a sequence-specific transcriptional repressor binding 5'-GACTNGACT-3' in regulatory regions of c-myc, bcl-2, and Hox genes [PMID:8521824], and it homodimerizes through its N-terminal RING and alpha-helix domains in a phosphorylation-regulated manner [PMID:12480532]. It restrains cell-cycle progression through a c-Myc/CDC25 cascade and through PI3K/Akt-cyclin D1/p27 signaling, and it transcriptionally represses Bmi-1, thereby limiting self-renewal and driving senescence [PMID:9806630, PMID:17151361, PMID:18519679]. Independent of chromatin, PCGF2 sequesters the SUMO E2 enzyme UBC9/UBE2I to inhibit SUMOylation of substrates including HSF2, RanGAP1, and PML-RARA [PMID:18211895, PMID:18706886, PMID:27030546]. Across multiple cancers PCGF2 behaves as a tumor suppressor by repressing Bmi-1, HIF-1α/VEGF, and EMT programs and by controlling ESR1 expression [PMID:17151361, PMID:21602890, PMID:23474752, PMID:25822021], and it is required for HSC self-renewal restraint, T-cell differentiation, and granulosa-cell folliculogenesis [PMID:9806630, PMID:11520462, PMID:36407101]. De novo missense mutations at Pro65 of PCGF2 cause Turnpenny-Fry syndrome [PMID:30343942].","teleology":[{"year":1993,"claim":"Establishing the molecular nature of MEL-18 was the first step: defining it as a nuclear RING-finger protein placed it among chromatin-associated regulators rather than cytoplasmic effectors.","evidence":"cDNA cloning, sequence analysis, and in situ hybridization mapping to 12q22","pmids":["8325509"],"confidence":"Medium","gaps":["Domain function not tested","No binding partners or substrates identified","No functional assay"]},{"year":1995,"claim":"The question of how MEL-18 acts on genes was first answered by showing it is a sequence-specific DNA-binding repressor, suggesting a direct route to target-gene silencing.","evidence":"In vitro DNA binding and transcriptional reporter assays defining the 5'-GACTNGACT-3' motif","pmids":["8521824"],"confidence":"Medium","gaps":["In vivo occupancy at endogenous loci not shown","Relationship to PRC1 silencing unresolved","Repression cofactors unknown"]},{"year":1996,"claim":"Genetic knockout established MEL-18 as a bona fide Polycomb group gene required to maintain Hox silencing during axial patterning, anchoring its developmental function.","evidence":"Homologous-recombination knockout mice with skeletal analysis and Hox in situ hybridization","pmids":["8625838"],"confidence":"High","gaps":["Molecular mechanism of silencing not defined","Complex membership not yet established","Direct vs indirect Hox regulation unclear"]},{"year":1998,"claim":"Knockout and double-transgenic epistasis answered how MEL-18 controls proliferation, placing c-Myc downstream in a cell-cycle-restraining cascade and linking it genetically to bmi-1.","evidence":"Transgenic and double-transgenic mice with CDK assays, Western blotting, flow cytometry; epistasis with bmi-1 mutants","pmids":["9806630","9252126"],"confidence":"High","gaps":["Direct vs indirect c-Myc regulation not resolved here","Chromatin mechanism not addressed","Tissue specificity of cascade unclear"]},{"year":2004,"claim":"Reciprocal gain/loss-of-function in stem and progenitor cells established MEL-18 as a negative regulator of self-renewal acting through defined Hox/Notch targets, extending its role from patterning to cell-fate maintenance.","evidence":"Knockout/transgenic mice, competitive repopulation, RT-PCR for Hoxb4 (HSC) and Hes-1/Notch in T progenitors; IL-4/GATA3 demethylation in Th2","pmids":["15183898","15728456","11520462"],"confidence":"High","gaps":["Whether effects are PRC1-dependent not directly tested","Direct chromatin binding at these loci not all shown","Mechanism of epigenetic memory undefined"]},{"year":2006,"claim":"Direct demonstration that MEL-18 represses Bmi-1 transcription clarified the seemingly paradoxical relationship between two PcG genes and linked MEL-18 to senescence and tumor suppression.","evidence":"Promoter-reporter, ChIP, RT-PCR, RNAi, and overexpression in human fibroblasts","pmids":["17151361"],"confidence":"High","gaps":["Whether repression is PRC1-mediated not resolved","Contribution of direct vs c-Myc-dependent route not quantified"]},{"year":2007,"claim":"Biochemical reconstitution answered the central mechanistic question of MEL-18's enzymatic role: it forms a PRC1-like complex and directs the Ring1B E3 ligase to monoubiquitylate H2AK119, with this targeting requiring MEL-18 phosphorylation.","evidence":"Affinity purification/MS, in vitro reconstitution of E3 ligase activity on nucleosomes, mutational and phosphorylation mapping","pmids":["17936708"],"confidence":"High","gaps":["Kinases responsible for required phosphorylation not identified","Genome-wide targeting rules not defined","Structural basis of H2AK119 specificity unresolved"]},{"year":2008,"claim":"Discovery of UBC9 sequestration revealed a chromatin-independent activity: MEL-18 inhibits SUMOylation of specific substrates, with cell-cycle-modulated interactions explaining mitotic SUMOylation changes.","evidence":"Reciprocal Co-IP, gain/loss-of-function, and in vitro SUMOylation assays for HSF2 and RanGAP1; domain mapping","pmids":["18211895","18706886"],"confidence":"High","gaps":["Full substrate repertoire unknown","How UBC9 sequestration is regulated mechanistically unclear","Relationship to PRC1 function not integrated"]},{"year":2013,"claim":"A series of cancer studies established MEL-18 as a tumor suppressor acting through multiple downstream axes—Akt/Bmi-1, HIF-1α/VEGF angiogenesis, and miR-205/ZEB-driven EMT.","evidence":"Knockdown/overexpression with pathway readouts, ChIP, DNA-methylation analysis, reporter assays, and xenografts in breast cancer models","pmids":["17545584","21602890","23474752","22954590"],"confidence":"Medium","gaps":["Direct vs indirect targets not fully separated","Reliance on single-lab breast cancer models","In vivo causal hierarchy among axes unresolved"]},{"year":2016,"claim":"Extending the SUMO-inhibitory role, MEL-18 was shown to control SUMOylation of disease-relevant substrates (PML-RARA) and of ERα transactivators, linking the activity to leukemia therapy response and estrogen-dependent breast cancer.","evidence":"Co-IP, immunofluorescence, SUMOylation/ubiquitylation assays, reporter assays, and xenografts; ATO disruption of the PCGF2-UBE2I interaction","pmids":["27030546","25822021"],"confidence":"Medium","gaps":["Generalizability beyond tested substrates unknown","Structural basis of UBE2I inhibition undefined","Balance between chromatin and SUMO functions in vivo unclear"]},{"year":2018,"claim":"Human genetics tied PCGF2 to a defined developmental disorder, with recurrent Pro65 missense changes proposed to act dominant-negatively on PRC1-histone engagement.","evidence":"De novo missense mutations in 13 Turnpenny-Fry syndrome patients with computational structural modeling","pmids":["30343942"],"confidence":"Low","gaps":["Dominant-negative mechanism is modeled, not experimentally confirmed","Effect on H2AK119ub not measured","Genotype-phenotype mechanism untested in cells"]},{"year":2024,"claim":"Genomic and conditional-knockout studies refined the chromatin function, showing cPRC1.2 forms loops at bivalent promoters and controls neural/granulosa-cell fate via locus-specific H2AK119ub rather than global ubiquitylation.","evidence":"Conditional knockout (folliculogenesis/Pgr), CRISPR knockout in ESCs/NSCs, Hi-C, ChIP-seq for H2AK119ub1 and CTCF, RNA-seq","pmids":["36407101","bio_10.1101_2024.11.13.623456","bio_10.1101_2024.08.07.606990"],"confidence":"Medium","gaps":["Two ESC/NSC studies are preprints","Mechanism of loop formation vs ubiquitylation not separated","How CTCF and cPRC1.2 anchors interconvert undefined"]},{"year":null,"claim":"How PCGF2's chromatin (PRC1/H2AK119ub) and chromatin-independent (UBC9 sequestration, sequence-specific repression) activities are coordinated, and which kinases license its substrate-targeting phosphorylation, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model integrating PRC1 and SUMO-inhibitory roles","Kinases controlling MEL-18 phosphorylation unidentified","Structural basis of H2AK119 targeting and Pro65 dysfunction unsolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[12,27]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,11,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,16,24]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12,27,28]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,11,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,27,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,16,24]}],"complexes":["canonical PRC1 (cPRC1.2)","melPRC1 (Ring1B/Mel-18/HPH2/CBX8)"],"partners":["RING1B","CBX8","UBE2I","HSF2","RANGAP1","PML-RARA","CYCLIN D2","LAMIN A/C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35227","full_name":"Polycomb group RING finger protein 2","aliases":["DNA-binding protein Mel-18","RING finger protein 110","Zinc finger protein 144"],"length_aa":344,"mass_kda":37.8,"function":"Transcriptional repressor. 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Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P35227/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PCGF2","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PCGF2","total_profiled":1310},"omim":[{"mim_id":"618371","title":"TURNPENNY-FRY SYNDROME; TPFS","url":"https://www.omim.org/entry/618371"},{"mim_id":"617407","title":"POLYCOMB GROUP RING FINGER PROTEIN 5; PCGF5","url":"https://www.omim.org/entry/617407"},{"mim_id":"610231","title":"POLYCOMB GROUP RING FINGER PROTEIN 1; PCGF1","url":"https://www.omim.org/entry/610231"},{"mim_id":"605590","title":"SPLICING FACTOR 3B, SUBUNIT 1; SF3B1","url":"https://www.omim.org/entry/605590"},{"mim_id":"600346","title":"POLYCOMB GROUP RING FINGER PROTEIN 2; PCGF2","url":"https://www.omim.org/entry/600346"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PCGF2"},"hgnc":{"alias_symbol":["MEL-18"],"prev_symbol":["ZNF144","RNF110"]},"alphafold":{"accession":"P35227","domains":[{"cath_id":"3.30.40.10","chopping":"8-120","consensus_level":"medium","plddt":92.0865,"start":8,"end":120},{"cath_id":"3.10.20.90","chopping":"129-141_162-230","consensus_level":"high","plddt":93.4289,"start":129,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35227","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35227-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35227-F1-predicted_aligned_error_v6.png","plddt_mean":73.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PCGF2","jax_strain_url":"https://www.jax.org/strain/search?query=PCGF2"},"sequence":{"accession":"P35227","fasta_url":"https://rest.uniprot.org/uniprotkb/P35227.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35227/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35227"}},"corpus_meta":[{"pmid":"8625838","id":"PMC_8625838","title":"A 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\"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA binding demonstrated with functional transcriptional repression, single lab but two orthogonal methods\",\n      \"pmids\": [\"8521824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The MEL-18 (PCGF2) protein contains a RING-finger motif, a helix-loop-helix (HLH)-like structure, and a Pro/Ser-rich region, and the protein localizes to the nucleus. The human gene maps to chromosome 12q22.\",\n      \"method\": \"cDNA cloning, sequence analysis, in situ hybridization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and structural characterization with chromosomal mapping by two orthogonal methods\",\n      \"pmids\": [\"8325509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mel-18 knockout mice display posterior homeotic transformations of the axial skeleton with ectopic expression of Hox cluster genes, establishing Mel-18 (PCGF2) as a Polycomb group gene required to maintain Hox gene silencing in paraxial mesoderm.\",\n      \"method\": \"Homologous recombination knockout mice, skeletal analysis, in situ hybridization for Hox gene expression\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined molecular phenotype (ectopic Hox expression), replicated across multiple mutant animals\",\n      \"pmids\": [\"8625838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mel-18 (PCGF2) loss-of-function results in severe combined immunodeficiency due to impaired mitotic response of lymphocyte precursors to IL-7 stimulation; the identical phenotype in mel-18 and bmi-1 mutants places them in the same genetic cascade controlling cell cycle progression in the immune system.\",\n      \"method\": \"Knockout mice, lymphocyte proliferation assays, genetic epistasis (mel-18 vs bmi-1 mutant comparison)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular phenotype and genetic epistasis analysis across two independent mutants\",\n      \"pmids\": [\"9252126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mel-18 (PCGF2) negatively regulates cell cycle progression via a c-Myc/CDC25 cascade; overexpression arrests B cells at G1 with downregulation of c-Myc, cyclins D2/E, and CDKs, and this arrest is rescued in mel-18/c-myc double-transgenic mice, placing c-Myc downstream of Mel-18.\",\n      \"method\": \"Transgenic mice, double-transgenic epistasis, Western blotting, CDK activity assays, flow cytometry\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double-transgenic rescue, multiple biochemical readouts in a single rigorous study\",\n      \"pmids\": [\"9806630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mel-18 (PCGF2) is required for Th2 cell differentiation; mel-18 knockout T cells show defective IL-4 gene demethylation and reduced GATA3 induction, placing Mel-18 upstream of epigenetic remodeling at the IL-4 locus during Th2 polarization.\",\n      \"method\": \"Knockout mice, cytokine production assays, DNA methylation analysis, GATA3 expression analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple orthogonal mechanistic readouts (DNA methylation, transcription factor expression, cytokine production)\",\n      \"pmids\": [\"11520462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mel-18 (PCGF2) forms homodimers requiring the N-terminal RING-finger and alpha-helix domains; homodimerization is regulated by phosphorylation state, with dephosphorylated Mel-18 able to homodimerize, and this is controlled by PKC and phosphatases.\",\n      \"method\": \"In vitro pull-down assays, co-immunoprecipitation in transfected COS-7 cells, deletion analysis, PKC inhibitor/phosphatase experiments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vitro and in vivo pulldowns with deletion mapping and pharmacological modulation, single lab\",\n      \"pmids\": [\"12480532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mel-18 (PCGF2) negatively regulates hematopoietic stem cell self-renewal; mel-18 knockout HSCs show elevated Hoxb4 expression, increased G0 phase proportion, and enhanced long-term reconstitution activity, while mel-18 transgenic mice show the opposite.\",\n      \"method\": \"Knockout and transgenic mice, competitive repopulation assays, quantitative RT-PCR for Hoxb4, cell cycle analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with defined molecular target (Hoxb4) and functional in vivo readout\",\n      \"pmids\": [\"15183898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mel-18 (PCGF2) supports early T progenitor expansion by maintaining Hes-1 expression, a Notch pathway target; mel-18 knockout early T progenitors fail to maintain Notch-induced Hes-1 expression, placing Mel-18 as a required epigenetic memory component for Notch-driven transcription.\",\n      \"method\": \"Knockout mice, in vivo and in vitro T progenitor assays, quantitative RT-PCR for Hes-1, Delta-like-1 co-culture\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with mechanistic target (Hes-1) identified, single lab with two experimental systems (in vivo and in vitro)\",\n      \"pmids\": [\"15728456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mel-18 (PCGF2) directly interacts with cyclin D2 via its C-terminal proline/serine-rich domain (P/S domain), and Mel-18 inhibits cyclin D2 activity; knockdown of Mel-18 in cyclin D2-overexpressing cells increases proliferative activity.\",\n      \"method\": \"Yeast two-hybrid screen, co-localization studies, deletion mapping, antisense knockdown with proliferation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-localization plus functional knockdown, single lab, binding domain mapped\",\n      \"pmids\": [\"16182291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MEL-18 (PCGF2) was identified as a novel lamin A/C-interacting protein by yeast two-hybrid; co-immunoprecipitation of endogenous proteins did not show differential binding between normal and progerin (HGPS mutant lamin A), indicating no unique interaction with progerin.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid identification with endogenous co-IP showing no differential binding; interaction confirmed but context is non-specific\",\n      \"pmids\": [\"16248985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mel-18 (PCGF2) transcriptionally represses Bmi-1 expression, and this repression of Bmi-1 by Mel-18 mediates accelerated cellular senescence and shortening of replicative lifespan; Mel-18 also down-regulates c-Myc, which in turn controls Bmi-1 expression.\",\n      \"method\": \"Promoter-reporter assays, chromatin immunoprecipitation, quantitative RT-PCR, RNA interference, overexpression in human fibroblasts\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, promoter reporter, ChIP, RNAi) in a single rigorous study establishing direct transcriptional regulation\",\n      \"pmids\": [\"17151361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MEL-18 (PCGF2) forms a PRC1-like complex (melPRC1) containing RING1/2, HPH2, and CBX8; a reconstituted Ring1B/Mel-18 subcomplex functions as an E3 ubiquitin ligase that ubiquitylates histone H2A specifically at lysine 119 in nucleosomes, with Ring1B providing E3 catalytic activity and Mel-18 directing specificity to H2AK119 in chromatin. This substrate-targeting function requires prior phosphorylation of Mel-18 at multiple residues.\",\n      \"method\": \"Affinity purification/mass spectrometry, in vitro reconstitution of E3 ligase activity, nucleosome ubiquitylation assay, mutational analysis, phosphorylation mapping\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of E3 ligase with nucleosome substrates, mutagenesis, phosphorylation analysis, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"17936708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mel-18 (PCGF2) represses Bmi-1 expression and consequently down-regulates Akt/PKB activity in breast cancer cells; constitutively active Akt overrides the tumor-suppressive effect of Mel-18, placing Akt downstream of the Mel-18→Bmi-1 axis.\",\n      \"method\": \"Overexpression, RNA interference knockdown, Akt kinase activity assays, constitutively active Akt rescue experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue with constitutively active Akt, RNAi and overexpression, single lab\",\n      \"pmids\": [\"17545584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Bmi-1 and Mel-18 (PCGF2) form complexes with overlapping protein compositions in cancer cells, and their knockdown produces similar effects on medulloblastoma cell proliferation and tumor formation, suggesting shared functional roles in cancer cell growth.\",\n      \"method\": \"Proteomics-based complex characterization, shRNA knockdown, clonogenic survival, anchorage-independent growth, xenograft tumor formation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-based complex characterization plus functional knockdown with in vivo readout, single lab\",\n      \"pmids\": [\"17452456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MEL-18 (PCGF2) interacts with HSF2 and inhibits HSF2 sumoylation by binding to and inhibiting the SUMO E2 enzyme UBC9; MEL-18 overexpression decreases and RNAi-mediated knockdown increases HSF2 sumoylation. The MEL-18/HSF2 interaction decreases during mitosis, explaining elevated mitotic HSF2 sumoylation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, RNA interference, in vitro sumoylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, gain- and loss-of-function with biochemical readout, in vitro activity assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18211895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MEL-18 (PCGF2) interacts with RanGAP1 and inhibits its sumoylation independently of the Mel-18 RING domain; RanGAP1 sumoylation decreases during mitosis concomitant with increased MEL-18/RanGAP1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, sumoylation assays, cell cycle fractionation, domain deletion analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional sumoylation assay and domain mapping, single lab\",\n      \"pmids\": [\"18706886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mel-18 (PCGF2) negatively regulates cell cycle G1-S progression in breast cancer through the PI3K/Akt pathway via cyclin D1 down-regulation and p27(Kip1) phosphorylation at Thr157, independent of INK4a/ARF genes; Mel-18 reduces Akt phosphorylation at Ser473, inhibits GSK-3β phosphorylation, reduces β-catenin nuclear localization, and lowers TCF/LEF promoter activity.\",\n      \"method\": \"Overexpression, antisense knockdown, flow cytometry, CDK activity assays, Western blotting, luciferase reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with multiple pathway readouts, single lab\",\n      \"pmids\": [\"18519679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PCGF2 (Mel-18) binds directly to HOXA7 chromatin and represses HOXA7 expression, acting upstream of HOXA7 in PRC1-mediated suppression of granulocytic differentiation in HL-60 cells; PCGF2 silencing de-represses HOXA7 and is sufficient to induce granulocytic differentiation.\",\n      \"method\": \"shRNA knockdown, chromatin immunoprecipitation (ChIP), differentiation marker assays, NBT staining, cell cycle analysis, overexpression of HOXA7\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct chromatin binding plus functional epistasis analysis, single lab\",\n      \"pmids\": [\"22085718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mel-18 (PCGF2) negatively regulates HIF-1α protein level and VEGF transcription via the PTEN/PI3K/Akt/MDM2 pathway; Mel-18 loss downregulates PTEN, activates PI3K/Akt/MDM2, increases HIF-1α, and retains FOXO3a in the cytoplasm, promoting HIF-1α/CBP complex recruitment to the VEGF promoter and tumor angiogenesis.\",\n      \"method\": \"Knockdown, overexpression, Western blotting, luciferase reporter assays, tube formation assays, in vivo xenograft experiments with microvessel density quantification\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway components tested with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"21602890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mel-18 (PCGF2) binding at the Il17a promoter positively regulates IL-17a and IL-17f expression in Th17 cells; Mel-18 binding is inducible, dependent on TCR signaling, requires continuous TGF-β for maintenance, and correlates with RORγt recruitment to the Il17a promoter.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), RNAi knockdown, cytokine expression assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding correlated with RORγt recruitment, RNAi validation, single lab\",\n      \"pmids\": [\"21674483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mel-18 (PCGF2) loss activates Wnt/TCF-mediated upregulation of Jagged-1 (a Notch ligand) and consequently activates Notch signaling to expand breast cancer stem cells; Mel-18 knockdown enriches CD44+/CD24−/ESA+ CSC populations and increases self-renewal, while pharmacologic inhibition of Notch or Wnt abrogates these effects.\",\n      \"method\": \"shRNA knockdown, overexpression, side population assay, tumorsphere formation, in vivo tumor-initiating assay, pharmacologic pathway inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"22954590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mel-18 (PCGF2) epigenetically regulates miR-205 transcription by inhibiting DNMT-mediated DNA methylation of the miR-205 promoter; Mel-18 loss promotes DNA methylation at this locus, reducing miR-205, which de-represses ZEB1 and ZEB2, promoting EMT and reducing E-cadherin expression in breast cancer cells.\",\n      \"method\": \"miRNA microarray, ChIP, DNA methylation analysis (bisulfite/DNMT inhibition), overexpression, knockdown, xenograft experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, DNA methylation analysis, microRNA functional assays, in vivo), single lab\",\n      \"pmids\": [\"23474752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MEL-18 (PCGF2) suppresses SUMOylation of ESR1 transactivators p53 and SP1, driving ESR1 transcription; MEL-18 facilitates deSUMOylation by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SENP1 (a SUMO protease). Loss of MEL-18 leads to ER-α downregulation and estrogen-independent breast cancer growth.\",\n      \"method\": \"Overexpression, knockdown, SUMOylation assays, ubiquitination assays, promoter reporter assays, in vivo xenograft experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical pathway dissection with multiple orthogonal methods and in vivo validation, single lab\",\n      \"pmids\": [\"25822021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PCGF2 (Mel-18) directly interacts with UBE2I (the SUMO E2) and inhibits UBE2I-mediated sumoylation of PML-RARA; PCGF2 knockdown alone is sufficient to induce sumoylation-, ubiquitylation- and PML-NB-mediated degradation of PML-RARA, and ATO treatment disrupts the PCGF2-UBE2I interaction, allowing UBE2I to access PML-RARA.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, overexpression, knockdown, sumoylation assays, ubiquitylation assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP confirmed with functional sumoylation and ubiquitylation assays, single lab\",\n      \"pmids\": [\"27030546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Missense mutations at Pro65 of PCGF2 cause a developmental syndrome (Turnpenny-Fry syndrome); computational structural modeling suggests the Pro65 substitutions alter an N-terminal loop critical for histone binding, potentially exerting dominant-negative effects by sequestering PRC1 components into complexes that cannot efficiently interact with histones.\",\n      \"method\": \"Clinical genetics (de novo missense mutations in 13 patients), computer structural modeling\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — structural mechanism is computational prediction only; human genetics establishes disease association but molecular mechanism is modeled not experimentally confirmed\",\n      \"pmids\": [\"30343942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEL-18 (PCGF2) epigenetically silences ADAM10/17 expression in cooperation with PRC1 and PRC2; MEL-18 loss de-represses ADAM10/17, increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization, thereby causing trastuzumab resistance in HER2+ breast cancer cells.\",\n      \"method\": \"Gene expression microarray, RTK array, shRNA knockdown, overexpression, in vivo xenograft experiments, FISH for MEL-18 amplification, pharmacologic ADAM inhibitor combination experiments\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic silencing mechanism with in vitro and in vivo rescue by pharmacologic inhibition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30265336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PCGF2 is required in granulosa cells for folliculogenesis and ovulation; PCGF2 binds the progesterone receptor (Pgr) promoter and upregulates Pgr expression by modifying H2AK119ub1 following hCG stimulation, and GC-specific Pcgf2 knockout mice show follicle loss, ovulation defects, and subfertility.\",\n      \"method\": \"Conditional knockout mice, ChIP for PCGF2 promoter binding, H2AK119ub1 chromatin immunoprecipitation, qRT-PCR for Pgr and downstream targets, histological analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined molecular target (Pgr), ChIP demonstrating direct promoter binding and histone modification, in vivo phenotype\",\n      \"pmids\": [\"36407101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The canonical Pcgf2-containing PRC1 complex (cPRC1.2) forms chromatin loops at bivalent promoters in mouse ESCs; loss of Pcgf2 disrupts these loops without affecting global H2AK119ub1 levels and impairs transcriptional induction of neuronal differentiation genes; CTCF is enriched at cPRC1.2 loop anchors, and neuronal differentiation involves a transition from cPRC1.2-mediated to CTCF-mediated active loops.\",\n      \"method\": \"CRISPR/Cas9 knockout in mouse ESCs, Hi-C chromatin conformation analysis, virtual 4C, ChIP-seq for H2AK119ub1 and CTCF, RNA-seq, neuronal differentiation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomic methods in a clean genetic system; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.11.13.623456\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Canonical PRC1 containing Pcgf2/4 (cPRC1.2/1.4) plays a dominant role over non-canonical PRC1 (Pcgf3/5) in regulating neural stem cell (NSC) proliferation and lineage fate; Pcgf2/4 deletion leads to strong reduction in NSC proliferation and altered neurogenic and gliogenic fate, with stem cell and neurogenic factor genes directly bound by PRC1 and differentially expressed upon deletion.\",\n      \"method\": \"CRISPR/Cas9 deletion in NSCs, side-by-side comparison of Pcgf2/4 vs Pcgf3/5 knockouts, RNA-seq, PRC1 ChIP-seq, proliferation and differentiation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic comparison with molecular target identification by ChIP-seq, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.08.07.606990\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PCGF2 (MEL-18) is a Polycomb group RING-finger protein that functions as a core component of canonical PRC1 complexes, where it directs the Ring1B E3 ubiquitin ligase activity specifically to H2AK119 in chromatin (requiring Mel-18 phosphorylation), represses Hox and other target genes to control axial patterning and cell fate, forms chromatin loops at bivalent promoters to maintain genes poised for activation, acts as a sequence-specific transcriptional repressor (binding 5'-GACTNGACT-3'), negatively regulates cell cycle progression through a c-Myc/CDC25 cascade and via Akt/cyclin D1/p27 signaling, inhibits SUMO conjugation by sequestering the E2 enzyme UBC9 to block sumoylation of HSF2, RanGAP1, and PML-RARA, and suppresses Bmi-1 transcription (partly via c-Myc downregulation) to function as a tumor suppressor in multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PCGF2 (MEL-18) is a Polycomb group RING-finger protein that operates as a core subunit of canonical PRC1 to enforce chromatin-based transcriptional silencing controlling axial patterning, cell-fate decisions, and proliferation [#2, #12]. Within a melPRC1 complex containing RING1/2, HPH2, and CBX8, PCGF2 directs the Ring1B E3 ubiquitin ligase to monoubiquitylate nucleosomal histone H2A specifically at lysine 119, a substrate-targeting function requiring prior phosphorylation of PCGF2 [#12]; this PRC1 activity loops bivalent promoters and represses target genes including the Hox cluster, with genetic loss causing posterior homeotic transformation and ectopic Hox expression [#2, #28]. PCGF2 also acts as a sequence-specific transcriptional repressor binding 5'-GACTNGACT-3' in regulatory regions of c-myc, bcl-2, and Hox genes [#0], and it homodimerizes through its N-terminal RING and alpha-helix domains in a phosphorylation-regulated manner [#6]. It restrains cell-cycle progression through a c-Myc/CDC25 cascade and through PI3K/Akt-cyclin D1/p27 signaling, and it transcriptionally represses Bmi-1, thereby limiting self-renewal and driving senescence [#4, #11, #17]. Independent of chromatin, PCGF2 sequesters the SUMO E2 enzyme UBC9/UBE2I to inhibit SUMOylation of substrates including HSF2, RanGAP1, and PML-RARA [#15, #16, #24]. Across multiple cancers PCGF2 behaves as a tumor suppressor by repressing Bmi-1, HIF-1\\u03b1/VEGF, and EMT programs and by controlling ESR1 expression [#11, #19, #22, #23], and it is required for HSC self-renewal restraint, T-cell differentiation, and granulosa-cell folliculogenesis [#4, #5, #27]. De novo missense mutations at Pro65 of PCGF2 cause Turnpenny-Fry syndrome [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the molecular nature of MEL-18 was the first step: defining it as a nuclear RING-finger protein placed it among chromatin-associated regulators rather than cytoplasmic effectors.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and in situ hybridization mapping to 12q22\",\n      \"pmids\": [\"8325509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain function not tested\", \"No binding partners or substrates identified\", \"No functional assay\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The question of how MEL-18 acts on genes was first answered by showing it is a sequence-specific DNA-binding repressor, suggesting a direct route to target-gene silencing.\",\n      \"evidence\": \"In vitro DNA binding and transcriptional reporter assays defining the 5'-GACTNGACT-3' motif\",\n      \"pmids\": [\"8521824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo occupancy at endogenous loci not shown\", \"Relationship to PRC1 silencing unresolved\", \"Repression cofactors unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Genetic knockout established MEL-18 as a bona fide Polycomb group gene required to maintain Hox silencing during axial patterning, anchoring its developmental function.\",\n      \"evidence\": \"Homologous-recombination knockout mice with skeletal analysis and Hox in situ hybridization\",\n      \"pmids\": [\"8625838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of silencing not defined\", \"Complex membership not yet established\", \"Direct vs indirect Hox regulation unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Knockout and double-transgenic epistasis answered how MEL-18 controls proliferation, placing c-Myc downstream in a cell-cycle-restraining cascade and linking it genetically to bmi-1.\",\n      \"evidence\": \"Transgenic and double-transgenic mice with CDK assays, Western blotting, flow cytometry; epistasis with bmi-1 mutants\",\n      \"pmids\": [\"9806630\", \"9252126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect c-Myc regulation not resolved here\", \"Chromatin mechanism not addressed\", \"Tissue specificity of cascade unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reciprocal gain/loss-of-function in stem and progenitor cells established MEL-18 as a negative regulator of self-renewal acting through defined Hox/Notch targets, extending its role from patterning to cell-fate maintenance.\",\n      \"evidence\": \"Knockout/transgenic mice, competitive repopulation, RT-PCR for Hoxb4 (HSC) and Hes-1/Notch in T progenitors; IL-4/GATA3 demethylation in Th2\",\n      \"pmids\": [\"15183898\", \"15728456\", \"11520462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether effects are PRC1-dependent not directly tested\", \"Direct chromatin binding at these loci not all shown\", \"Mechanism of epigenetic memory undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Direct demonstration that MEL-18 represses Bmi-1 transcription clarified the seemingly paradoxical relationship between two PcG genes and linked MEL-18 to senescence and tumor suppression.\",\n      \"evidence\": \"Promoter-reporter, ChIP, RT-PCR, RNAi, and overexpression in human fibroblasts\",\n      \"pmids\": [\"17151361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether repression is PRC1-mediated not resolved\", \"Contribution of direct vs c-Myc-dependent route not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Biochemical reconstitution answered the central mechanistic question of MEL-18's enzymatic role: it forms a PRC1-like complex and directs the Ring1B E3 ligase to monoubiquitylate H2AK119, with this targeting requiring MEL-18 phosphorylation.\",\n      \"evidence\": \"Affinity purification/MS, in vitro reconstitution of E3 ligase activity on nucleosomes, mutational and phosphorylation mapping\",\n      \"pmids\": [\"17936708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases responsible for required phosphorylation not identified\", \"Genome-wide targeting rules not defined\", \"Structural basis of H2AK119 specificity unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of UBC9 sequestration revealed a chromatin-independent activity: MEL-18 inhibits SUMOylation of specific substrates, with cell-cycle-modulated interactions explaining mitotic SUMOylation changes.\",\n      \"evidence\": \"Reciprocal Co-IP, gain/loss-of-function, and in vitro SUMOylation assays for HSF2 and RanGAP1; domain mapping\",\n      \"pmids\": [\"18211895\", \"18706886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full substrate repertoire unknown\", \"How UBC9 sequestration is regulated mechanistically unclear\", \"Relationship to PRC1 function not integrated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A series of cancer studies established MEL-18 as a tumor suppressor acting through multiple downstream axes—Akt/Bmi-1, HIF-1\\u03b1/VEGF angiogenesis, and miR-205/ZEB-driven EMT.\",\n      \"evidence\": \"Knockdown/overexpression with pathway readouts, ChIP, DNA-methylation analysis, reporter assays, and xenografts in breast cancer models\",\n      \"pmids\": [\"17545584\", \"21602890\", \"23474752\", \"22954590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect targets not fully separated\", \"Reliance on single-lab breast cancer models\", \"In vivo causal hierarchy among axes unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending the SUMO-inhibitory role, MEL-18 was shown to control SUMOylation of disease-relevant substrates (PML-RARA) and of ER\\u03b1 transactivators, linking the activity to leukemia therapy response and estrogen-dependent breast cancer.\",\n      \"evidence\": \"Co-IP, immunofluorescence, SUMOylation/ubiquitylation assays, reporter assays, and xenografts; ATO disruption of the PCGF2-UBE2I interaction\",\n      \"pmids\": [\"27030546\", \"25822021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability beyond tested substrates unknown\", \"Structural basis of UBE2I inhibition undefined\", \"Balance between chromatin and SUMO functions in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Human genetics tied PCGF2 to a defined developmental disorder, with recurrent Pro65 missense changes proposed to act dominant-negatively on PRC1-histone engagement.\",\n      \"evidence\": \"De novo missense mutations in 13 Turnpenny-Fry syndrome patients with computational structural modeling\",\n      \"pmids\": [\"30343942\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Dominant-negative mechanism is modeled, not experimentally confirmed\", \"Effect on H2AK119ub not measured\", \"Genotype-phenotype mechanism untested in cells\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genomic and conditional-knockout studies refined the chromatin function, showing cPRC1.2 forms loops at bivalent promoters and controls neural/granulosa-cell fate via locus-specific H2AK119ub rather than global ubiquitylation.\",\n      \"evidence\": \"Conditional knockout (folliculogenesis/Pgr), CRISPR knockout in ESCs/NSCs, Hi-C, ChIP-seq for H2AK119ub1 and CTCF, RNA-seq\",\n      \"pmids\": [\"36407101\", \"bio_10.1101_2024.11.13.623456\", \"bio_10.1101_2024.08.07.606990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two ESC/NSC studies are preprints\", \"Mechanism of loop formation vs ubiquitylation not separated\", \"How CTCF and cPRC1.2 anchors interconvert undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PCGF2's chromatin (PRC1/H2AK119ub) and chromatin-independent (UBC9 sequestration, sequence-specific repression) activities are coordinated, and which kinases license its substrate-targeting phosphorylation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model integrating PRC1 and SUMO-inhibitory roles\", \"Kinases controlling MEL-18 phosphorylation unidentified\", \"Structural basis of H2AK119 targeting and Pro65 dysfunction unsolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [12, 27]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 11, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 16, 24]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12, 27, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 11, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 27, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 16, 24]}\n    ],\n    \"complexes\": [\"canonical PRC1 (cPRC1.2)\", \"melPRC1 (Ring1B/Mel-18/HPH2/CBX8)\"],\n    \"partners\": [\"RING1B\", \"CBX8\", \"UBE2I\", \"HSF2\", \"RanGAP1\", \"PML-RARA\", \"Cyclin D2\", \"Lamin A/C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}