Affinage

PCGF5

Polycomb group RING finger protein 5 · UniProt Q86SE9

Length
256 aa
Mass
29.7 kDa
Annotated
2026-06-10
30 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCGF5 is a subunit of a variant (non-canonical) Polycomb Repressive Complex 1 that controls the histone modifications H2AK119ub1 and H3K27me3 to direct lineage choice during differentiation (PMID:29765032, PMID:27136092). Loss of PCGF5 globally reduces H2AK119ub1 in vivo, establishing it as a bona fide effector of PRC1 histone-modifying activity (PMID:27136092). Its transcriptional output is context-dependent: in mouse ES cells PCGF5 represses the SMAD2/TGF-β pathway and resolves repressive marks around neural genes to permit neural differentiation (PMID:29765032), yet together with PCGF3 it can act as a transcriptional activator through the pluripotency factor Tex10 and the co-activator p300 and is required for mesoderm differentiation (PMID:29054931). PCGF5 partitions cell fate during embryoid body and germ-layer formation, modulating Nodal, Wnt, and Notch signaling (PMID:32130724), and governs neural stem cell fate by suppressing Wnt3 via the Notch1/Hes1 axis (PMID:38533065). Within these complexes PCGF5 partners with RYBP in an SCL/TAL1-driven program that silences alternative cardiac/paraxial lineage genes during blood specification (PMID:30560907) and with the long isoform of AUTS2, with which it exerts opposing transcriptional effects on the homeobox target MSX1 (PMID:27322685). PCGF5 is also a host target hijacked during Ehrlichia chaffeensis infection: the bacterial effector TRP120 functions as a HECT E3 ubiquitin ligase that polyubiquitinates PCGF5 in a Nedd4L-dependent manner, driving its proteasomal degradation, redistribution to the ehrlichial vacuole, and loss of PRC1-mediated repression of HOX loci (PMID:29358333, PMID:28630068).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2009 Medium

    Established the earliest physical link between PCGF5 and a pathogen effector, defining the tandem-repeat domain as the interaction module.

    Evidence Yeast two-hybrid, co-IP, and confocal colocalization of E. chaffeensis TRP47 with PCGF5 in HeLa cells

    PMID:19273555

    Open questions at the time
    • Functional consequence of the interaction for PCGF5 or infection not tested
    • No link to PCGF5's chromatin function established at this stage
  2. 2011 Medium

    Identified a second Ehrlichia effector, TRP120, as a PCGF5-binding protein, showing its TR domain is specifically sufficient for the interaction.

    Evidence Yeast two-hybrid cotransformation and fluorescence colocalization near ehrlichial morulae in HeLa cells

    PMID:21859857

    Open questions at the time
    • Mechanism of PCGF5 recruitment unresolved
    • No demonstration of effect on host transcription
  3. 2014 Medium

    Showed that PCGF5 recruitment to the pathogen inclusion is SUMO-dependent, defining a post-translational requirement for its relocalization during infection.

    Evidence Small-molecule SUMO pathway inhibition with confocal colocalization and co-IP in infected cells

    PMID:25047847

    Open questions at the time
    • Direct SUMO substrate (PCGF5 vs TRP120) not pinpointed
    • Consequence for PCGF5 chromatin targets not measured
  4. 2016 High

    Tested whether PCGF5 is required for its histone mark in vivo, revealing it is a global H2AK119ub1 modifier but functionally redundant in hematopoietic stem cells.

    Evidence Conditional Cre-ERT knockout in mice, competitive bone marrow transplantation, and H2AK119ub1 ChIP-seq

    PMID:27136092

    Open questions at the time
    • Identity of compensating PRC1-related complexes not defined
    • Did not reveal a non-redundant lineage context
  5. 2016 Medium

    Demonstrated context-specific repression by PCGF5 of a homeobox target, contrasting it with the activating activity of AUTS2 in the same complex subtype.

    Evidence Forced expression, EZH2 inhibition, and H3K27me3 ChIP on MSX1 in T-ALL cell lines

    PMID:27322685

    Open questions at the time
    • Direct PCGF5 occupancy at MSX1 not shown
    • Mechanism switching PCGF5 between repression and activation unresolved
  6. 2017 High

    Reconstituted the degradation mechanism, showing TRP120 itself is a HECT E3 ligase that polyubiquitinates PCGF5 via Nedd4L, explaining how the pathogen eliminates a host repressor.

    Evidence In vitro ubiquitination with purified TRP120 and E2 enzymes, HECT catalytic-site mutant, and Nedd4L siRNA knockdown

    PMID:28630068

    Open questions at the time
    • Ubiquitin chain linkage type on PCGF5 not specified
    • Whether endogenous PCGF5 turnover uses this pathway outside infection unknown
  7. 2017 High

    Reassigned PCGF5 (with PCGF3) as a potential transcriptional activator through Tex10/p300, broadening its role beyond repression and into mesoderm specification.

    Evidence CRISPR knockout, proteomic interactome (MS), promoter occupancy ChIP, and differentiation assays in ES cells

    PMID:29054931

    Open questions at the time
    • How PCGF5 toggles between activator and repressor not mechanistically resolved
    • PCGF5-specific vs PCGF3-shared contributions not fully separated
  8. 2018 High

    Placed PCGF5 causally in neural differentiation by showing its loss derepresses SMAD2/TGF-β signaling and blocks resolution of repressive marks at neural genes.

    Evidence CRISPR knockout in mESCs with RNA-seq, histone-mark ChIP-seq, and rescue

    PMID:29765032

    Open questions at the time
    • Direct PCGF5 targets among SMAD2 pathway genes not enumerated
    • Composition of the relevant PRC1 variant at neural loci not defined
  9. 2018 High

    Showed the infection consequences of PCGF5 loss: TRP120-driven nuclear-to-vacuole redistribution and proteasomal degradation that disrupts PRC1 repression of HOX loci and favors bacterial growth.

    Evidence Co-IP, confocal IF, siRNA knockdown with infection readout, proteasome inhibition, and H2AK119ub1 ChIP

    PMID:29358333

    Open questions at the time
    • Whether HOX derepression directly benefits the pathogen not established
    • Specific PCGF5-target genes among redistributed loci not isolated
  10. 2018 Medium

    Implicated PCGF5 in lineage exclusion and limb patterning, co-occupying SCL/RYBP target loci and contributing to a variant PRC1 that polarizes Meis2.

    Evidence Scl-null mouse model with RYBP/H2AK119ub1/H3K27me3 ChIP-seq, and mouse limb-bud genetic/modeling studies

    PMID:30190278 PMID:30560907

    Open questions at the time
    • PCGF5-specific contribution inferred from co-occupancy rather than direct PCGF5 knockout
    • Functional redundancy with PCGF3 not dissected
  11. 2020 Medium

    Extended PCGF5's role across all germ layers, linking its loss to altered Nodal/Wnt/Notch signaling and shifted cardiomyocyte vs neural-ectodermal fate.

    Evidence CRISPR knockout mESCs with embryoid body differentiation and pathway-level gene expression

    PMID:32130724

    Open questions at the time
    • Direct chromatin targets driving each signaling change not mapped
    • Single study, single lab
  12. 2024 Medium

    Defined a signaling mechanism for PCGF5 in neural stem cell fate via Notch1/Hes1-mediated suppression of Wnt3, validated across two model systems.

    Evidence siRNA knockdown/overexpression in P19 cells and zebrafish morpholino knockdown with marker and developmental readouts

    PMID:38533065

    Open questions at the time
    • Whether PCGF5 acts directly at Notch1/Hes1/Wnt3 loci via PRC1 marks not shown
    • Single lab
  13. 2025 Medium

    Implicated PCGF5 in the earliest embryonic chromatin program, linking it to ZGA, noncanonical imprinting, and Xist-mediated X regulation.

    Evidence Morpholino knockdown in mouse preimplantation embryos with H3K27me3/H2AK119ub1 ChIP and expression analysis (preprint)

    PMID:bio_10.1101_2025.01.24.632300

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Significance of the MT2C_Mm chimeric transcript unclear
    • Direct vs indirect effect on Xist region not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PCGF5 is switched between repressive (H2AK119ub1-depositing) and activating (Tex10/p300) modes at specific loci, and how its complex composition selects targets across distinct developmental contexts, remains unresolved.
  • No structural model of PCGF5-containing variant PRC1
  • Determinants of activator-vs-repressor choice undefined
  • Comprehensive direct target map across cell types lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2
Complex memberships
non-canonical PRC1 (PRC1.5/variant PRC1)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 PCGF5 is required for neural differentiation of mouse embryonic stem cells (mESCs); loss of PCGF5 blocks neural differentiation by activating the SMAD2/TGF-β signaling pathway and impairs reduction of H2AK119ub1 and H3K27me3 around neural-specific genes, keeping them repressed. CRISPR/Cas9 knockout in mESCs, RNA-seq, ChIP-seq, rescue experiments Nature communications High 29765032
2017 PCGF3 and PCGF5 function as transcriptional activators in ES cells through interaction with the pluripotency factor Tex10 and the co-activator p300; Pcgf3/5 deletion reduces Tex10 and p300 occupancy at target genes and globally reduces H2AK119ub1 levels; Pcgf3/5 are required for mesoderm differentiation. CRISPR/Cas9 knockout, RNA-seq, proteomic interactome (MS), ChIP/promoter occupancy analysis, in vitro and in vivo differentiation assays The Journal of biological chemistry High 29054931
2016 Pcgf5 deletion in hematopoietic stem and progenitor cells (HSPCs) causes significant reduction in global H2AK119ub1 levels but does not impair HSPC self-renewal or repopulating capacity, indicating that Pcgf5-containing PRC1 functions as a histone modifier in vivo but its role in HSPCs is compensated by other PRC1-related complexes. Conditional Cre-ERT knockout in mice, competitive bone marrow transplantation, ChIP-seq for H2AK119ub1, flow cytometry PloS one High 27136092
2018 During E. chaffeensis infection, the bacterial effector TRP120 interacts with PCGF5 (and other PCGF isoforms) in the nucleus early in infection; PCGF isoforms are redistributed from the nucleus to the ehrlichial vacuole and subsequently undergo proteasomal degradation; this disrupts PRC1-mediated H2AK119ub1 repressive marks and alters HOXB/HOXC gene transcription; siRNA knockdown of PCGF isoforms increases E. chaffeensis infection. Ectopic expression and co-immunoprecipitation of TRP120, confocal immunofluorescence microscopy, siRNA knockdown, proteasome inhibitor treatment, ChIP for H2AK119ub1 Infection and immunity High 29358333
2017 The E. chaffeensis effector TRP120 acts as a HECT E3 ubiquitin ligase that polyubiquitinates PCGF5, leading to reduced PCGF5 protein levels; this activity depends on Nedd4L, which also mediates TRP120 ubiquitination; Nedd4L knockdown reduces TRP120-Ub, decreases ehrlichial infection, and reduces PCGF5 recruitment to ehrlichial inclusions. In vitro ubiquitination assay with purified TRP120 and E2 enzymes, ectopic expression of HECT catalytic-site mutant, Nedd4L siRNA knockdown, immunoprecipitation Infection and immunity High 28630068
2018 During blood specification, SCL/TAL1 directly activates expression of PCGF5 (along with RYBP) as part of a Polycomb-PRC1 co-repressor program that suppresses alternative cardiac/paraxial lineage gene expression; PCGF5 and RYBP co-occupy SCL target genes including cardiac/paraxial loci; reduction of Rybp expression mimics the Scl-null cardiac phenotype. Scl-null mouse model, RNA-seq, ChIP-seq for RYBP and H2AK119ub1/H3K27me3, genome-wide ChIP, genetic rescue (Eto2/Rybp knockdown) Nature communications Medium 30560907
2018 A variant PRC1 complex incorporating PCGF3 and PCGF5 represses Meis2 expression in the distal mouse forelimb bud; PcG factors and retinoic acid-related signals antagonize each other to polarize Meis2 expression along the proximal-distal axis. Mouse genetic models, mathematical modeling, in vivo gene expression analysis Development (Cambridge, England) Medium 30190278
2009 The E. chaffeensis TRP47 effector interacts with PCGF5; the amino-terminal truncated form of p47 containing tandem repeats interacts with PCGF5 but not with FYN, PTPN2, or CAP1, establishing that the TR domain of p47 is sufficient for PCGF5 interaction; interaction confirmed by co-immunoprecipitation and colocalization in HeLa cells. Yeast two-hybrid, co-immunoprecipitation, colocalization by confocal fluorescence microscopy in HeLa cells transfected with AcGFP1-p47 Infection and immunity Medium 19273555
2011 The E. chaffeensis TRP120 effector interacts with PCGF5; the TR domain of TRP120 is sufficient for interaction with PCGF5 specifically, while other host targets require additional TRP120 domains; TRP120 and PCGF5 strongly colocalize in HeLa cells and near ehrlichial morulae. Yeast two-hybrid cotransformation confirmation, colocalization by fluorescence microscopy in HeLa cells Infection and immunity Medium 21859857
2019 PCGF5 interacts exclusively with the long isoform of AUTS2 (not the short isoform), as identified by yeast two-hybrid screen; PCGF3 expression levels influence the ability of the long AUTS2 isoform to activate or repress transcription, placing PCGF5 in the long-isoform-specific AUTS2-PRC1 complex. Yeast two-hybrid screen, reporter transcriptional assays Molecular psychiatry Low 30953002
2014 SUMO pathway inhibition significantly reduced recruitment of PCGF5 to E. chaffeensis ehrlichial inclusions (TRP120-interacting protein), demonstrating that SUMO-dependent interactions are required for PCGF5 localization to the bacterial inclusion during infection. Small-molecule SUMO pathway inhibitor treatment, confocal colocalization microscopy, co-immunoprecipitation Infection and immunity Medium 25047847
2016 In T-ALL cells, PCGF5 represses transcription of the NKL homeobox gene MSX1, while AUTS2 (as part of PRC1.5/PRC1 subtype 5) activates it; expression profiling and functional analyses demonstrate opposing activities of PCGF5 and AUTS2 on MSX1 transcription. Expression profiling, forced-expression experiments, pharmacological EZH2 inhibition, H3K27me3 ChIP analysis in T-ALL cell lines Oncotarget Medium 27322685
2024 Pcgf5 suppresses Wnt3 expression via activation of the Notch1/Hes1 signaling axis, thereby governing the differentiation fate of neural stem cells; knockdown of Pcgf5 in P19 cells decreases neuronal markers (Sox2, Zfp521, Pax6) while increasing pluripotency markers (Oct4, Nanog), and knockdown of pcgf5a by morpholino in zebrafish causes neurodevelopmental defects. siRNA knockdown and overexpression in P19 cells, zebrafish morpholino knockdown, qRT-PCR, in vivo neural marker analysis Heliyon Medium 38533065
2020 Pcgf5 knockout in mESCs delays generation of the three germ layers (especially ectoderm), impairs epithelial-mesenchymal transition during embryoid body morphogenesis, differentially affects Nodal and Wnt signaling gene expression, and induces repression of Notch pathway genes leading to enhanced cardiomyocyte maturation and dampened ectodermal-neural differentiation. CRISPR/Cas9 KO mESCs, embryoid body differentiation protocol, gene expression analysis Development, growth & differentiation Medium 32130724
2025 Pcgf5 forms a chimeric transcript with MT2C_Mm (MERVL long terminal repeat) during zygotic genome activation (ZGA); Pcgf5 knockdown reduces H3K27me3 and H2AK119ub1 in mouse preimplantation embryos, upregulates ZGA genes and imprinting genes, and impairs H3K27me3 addition to the maternal Xist region, implicating Pcgf5 in noncanonical imprinting and Xist regulation. Morpholino knockdown in mouse embryos, ChIP for H3K27me3 and H2AK119ub1, developmental rate tracking, gene expression analysis bioRxivpreprint Medium bio_10.1101_2025.01.24.632300
2023 PCGF5 is among a minority of Xist-recruited proteins that form Xist-seeded protein assemblies at the inactive X chromosome, placing it in the supramolecular assembly that drives X-chromosome inactivation. Protein assembly and localization analysis at the inactive X chromosome (described in the context of CIZ1-focused study) Frontiers in cell and developmental biology Low 38155839
2025 WDR68/DCAF7 interacts with PCGF5 (and AUTS2) as identified by co-immunoprecipitation coupled with LC-MS, placing PCGF5 in the WDR68 interactome relevant to mouse embryonic development. Co-immunoprecipitation combined with liquid chromatography-mass spectrometry (Co-IP/LC-MS) Journal of translational medicine Low 40462101

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 OstemiR: a novel panel of microRNA biomarkers in osteoblastic and osteocytic differentiation from mesencymal stem cells. PloS one 141 23533592
2020 Biological functions of chromobox (CBX) proteins in stem cell self-renewal, lineage-commitment, cancer and development. Bone 87 32979540
2013 Structure of the polycomb group protein PCGF1 in complex with BCOR reveals basis for binding selectivity of PCGF homologs. Structure (London, England : 1993) 87 23523425
2009 An Ehrlichia chaffeensis tandem repeat protein interacts with multiple host targets involved in cell signaling, transcriptional regulation, and vesicle trafficking. Infection and immunity 62 19273555
2014 Ehrlichia chaffeensis exploits host SUMOylation pathways to mediate effector-host interactions and promote intracellular survival. Infection and immunity 61 25047847
2018 PCGF5 is required for neural differentiation of embryonic stem cells. Nature communications 60 29765032
2011 Ehrlichia chaffeensis TRP120 interacts with a diverse array of eukaryotic proteins involved in transcription, signaling, and cytoskeleton organization. Infection and immunity 56 21859857
2019 AUTS2 isoforms control neuronal differentiation. Molecular psychiatry 44 30953002
2017 Polycomb group RING finger proteins 3/5 activate transcription via an interaction with the pluripotency factor Tex10 in embryonic stem cells. The Journal of biological chemistry 41 29054931
2018 SCL/TAL1 cooperates with Polycomb RYBP-PRC1 to suppress alternative lineages in blood-fated cells. Nature communications 31 30560907
2018 Evidence for functional interactions between the placenta and brain in pregnant mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 30521381
2018 NKL homeobox gene activities in B-cell development and lymphomas. PloS one 28 30308041
2018 Ehrlichia chaffeensis TRP120 Effector Targets and Recruits Host Polycomb Group Proteins for Degradation To Promote Intracellular Infection. Infection and immunity 25 29358333
2017 Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival. Infection and immunity 23 28630068
2014 RING finger proteins are involved in the progression of barrett esophagus to esophageal adenocarcinoma: a preliminary study. Gut and liver 21 25228972
2020 The genetic basis for PRC1 complex diversity emerged early in animal evolution. Proceedings of the National Academy of Sciences of the United States of America 20 32868440
2019 Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 19 31570769
2016 Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia. Oncotarget 16 27322685
2018 Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in the mouse distal forelimb bud. Development (Cambridge, England) 15 30190278
2016 Loss of Pcgf5 Affects Global H2A Monoubiquitination but Not the Function of Hematopoietic Stem and Progenitor Cells. PloS one 14 27136092
2020 Screening for reproductive biomarkers in Bactrian camel via iTRAQ analysis of proteomes. Reproduction in domestic animals = Zuchthygiene 13 31840896
2015 Knockdown of polycomb-group RING finger 6 modulates mouse male germ cell differentiation in vitro. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 9 25591775
2020 Polycomb group RING finger protein 5 influences several developmental signaling pathways during the in vitro differentiation of mouse embryonic stem cells. Development, growth & differentiation 6 32130724
2022 Transcriptional profiling of the chick retina identifies down-regulation of VIP and UTS2B genes during early lens-induced myopia. Molecular omics 5 35420081
2021 Alpha Enolase 1 Ubiquitination and Degradation Mediated by Ehrlichia chaffeensis TRP120 Disrupts Glycolytic Flux and Promotes Infection. Pathogens (Basel, Switzerland) 5 34451426
2024 Ehrlichia chaffeensis TRP120 ubiquitinates tumor suppressor APC to modulate Hippo and Wnt signaling. Frontiers in cell and developmental biology 2 38562145
2024 Pcgf5: An important regulatory factor in early embryonic neural induction. Heliyon 1 38533065
2023 CIZ1 in Xist seeded assemblies at the inactive X chromosome. Frontiers in cell and developmental biology 1 38155839
2025 Essential roles of DCAF7/WDR68 in mouse embryonic development. Journal of translational medicine 0 40462101
2025 TLX1 translocation variants and enhancer hijacking influence clinical outcome in T-cell acute lymphoblastic leukemia. HemaSphere 0 41473004

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