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Showing PHC1 — HPH1 is a alias.

PHC1

Polyhomeotic-like protein 1 · UniProt P78364

Length
1004 aa
Mass
105.5 kDa
Annotated
2026-06-10
48 papers in source corpus 15 papers cited in narrative 14 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

PHC1 (RAE28/HPH1/mph1) is a polyhomeotic-family subunit of canonical Polycomb Repressive Complex 1 (cPRC1) that enforces stable, heritable transcriptional repression during development through chromatin-based mechanisms (PMID:9571155, PMID:16024804). It assembles into large multimeric Polycomb complexes containing BMI1 and M33/CBX2, partly via its SAM/SPM domain, which self-associates and mediates heterotypic interactions with the SAM domains of Scm/SCMH1 and polyhomeotic (PMID:9571155, PMID:9499582, PMID:10653359); PHC1 also acts synergistically and dose-dependently with its paralog PHC2 at Hox loci (PMID:16024804). Functionally, PHC1 is required for the maintenance phase of developmental gene expression rather than its initiation: it sustains repressive Hoxb3 expression boundaries in the hindbrain and pharyngeal arches (PMID:11044623) and preserves the cardiac selector gene Nkx2.5, which acts as a downstream effector in cardiac morphogenesis (PMID:12122109, PMID:11950896). PHC1 sustains hematopoietic stem cell self-renewal and long-term repopulating activity and is required for the pro-B to pre-B lymphocyte transition (PMID:11164110, PMID:11901201, PMID:15245505). Loss-of-function mutation in PHC1 causes primary microcephaly, abolishing histone H2A ubiquitination, elevating Geminin, and impairing DNA damage repair, with all defects rescued by PHC1 re-expression (PMID:23418308). Beyond its PRC1 repressive role, PHC1 maintains pluripotency through a PRC1-independent mechanism in which it physically interacts with Nanog, activates Nanog transcription, and stabilizes chromatin interactions at the Nanog locus (PMID:33990559).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 Medium

    Established that PHC1 is a physical component of multimeric mammalian Polycomb complexes, defining its biochemical context as a chromatin repressor rather than a free-standing factor.

    Evidence Reciprocal Co-IP and gel filtration of mouse embryonic nuclear extracts with domain-deletion mapping

    PMID:9571155

    Open questions at the time
    • Complex composition varies by cell type and was not resolved at single-complex stoichiometry
    • Did not establish the catalytic activity of the assembled complex
  2. 1998 High

    Identified the SAM/SPM domain as the molecular interface mediating PHC1 self-association and binding to Scm and polyhomeotic, explaining how Polycomb subunits oligomerize.

    Evidence In vitro SAM domain binding assays with site-directed mutagenesis of interface residues

    PMID:9499582

    Open questions at the time
    • Interface mutagenesis was performed on ph SAM, not directly on PHC1
    • In vivo consequence of disrupting these interfaces not tested here
  3. 1998 Low

    Tested whether PHC1 has intrinsic sequence-specific DNA binding, reporting recognition of short consensus motifs by SELEX.

    Evidence GST-RAE28 pulldown with SELEX and oligonucleotide sequence analysis

    PMID:9861444

    Open questions at the time
    • Single in vitro binding assay with no mutagenesis or in vivo validation
    • Biological relevance of the identified motifs to PHC1 chromatin targeting unestablished
  4. 1999 Medium

    Extended the SAM-domain interaction repertoire by showing mammalian Scmh1 binds PHC1 via SPM domains, mirroring the conserved Drosophila ph-Scm architecture.

    Evidence In vitro SPM-domain protein interaction assay

    PMID:10653359

    Open questions at the time
    • Single in vitro method without reciprocal or in vivo confirmation
    • Functional consequence of the PHC1-Scmh1 interaction not addressed
  5. 1999 Medium

    Defined how PHC1's own gene is transcriptionally regulated, identifying inverted differentiation response sequences required for its induction during retinoic acid-driven differentiation.

    Evidence Reporter assays, EMSA, DNase I footprinting, and promoter mutagenesis in F9 cells

    PMID:10462505

    Open questions at the time
    • The DRS-binding transcription factors were not molecularly identified
    • Concerns PHC1 regulation, not PHC1 effector function
  6. 2000 Medium

    Resolved whether PHC1 establishes or maintains target repression, showing it is required to maintain — not initiate — Hoxb3 expression boundaries downstream of patterning regulators.

    Evidence In situ hybridization in rae28-knockout embryos with epistasis against kreisler/Krox20

    PMID:11044623

    Open questions at the time
    • Did not define the chromatin marks underlying the maintenance defect
    • Direct PHC1 occupancy at Hoxb3 not demonstrated
  7. 2001 Medium

    Demonstrated a dose-dependent requirement for PHC1 in lymphoid development, specifically the pro-B to pre-B transition, linking Polycomb maintenance to differentiation checkpoints.

    Evidence Chimeric mouse reconstitution, IL-7-dependent colony assay, and flow cytometry of B-cell stages

    PMID:11164110

    Open questions at the time
    • Target genes mediating the B-cell arrest not identified
    • Mechanistic link to chromatin repression at lymphoid loci not shown
  8. 2002 High

    Established PHC1 as a sustainer of hematopoietic stem cell self-renewal, quantifying severe loss of repopulating and self-renewal activity upon deletion.

    Evidence Competitive repopulation, serial transplantation, and LTC-IC assays

    PMID:11901201

    Open questions at the time
    • Molecular targets in HSCs not defined
    • Distinction between cell-autonomous and niche effects not fully resolved here
  9. 2002 High

    Placed Nkx2.5 as a genetic downstream effector of PHC1 in cardiac morphogenesis and showed PHC1 maintains Nkx2.5 expression through a non-cardiomyocyte pathway.

    Evidence Knockout phenotyping with NKX2.5 transgenic complementation and cell-type-specific rescue

    PMID:11950896 PMID:12122109

    Open questions at the time
    • The non-cardiomyocyte cell type through which PHC1 acts not identified
    • Direct chromatin regulation of the Nkx2.5 locus not shown
  10. 2003 Medium

    Revealed cell-cycle regulation of PHC1 chromatin association, showing it dissociates from chromatin during mitotic and meiotic prophase coincident with transcriptional arrest.

    Evidence Immunofluorescence of Rae28/Ph1 and Ring1B in mitotic U2-OS cells and meiotic mouse oocytes

    PMID:12883906

    Open questions at the time
    • Whether dissociation is cause or consequence of transcriptional arrest not determined
    • Mechanism driving the dissociation unknown
  11. 2005 High

    Demonstrated synergistic, dose-dependent cooperation between PHC1 and its paralog PHC2 within canonical PRC1 to repress Hox genes during anterior-posterior patterning.

    Evidence Reciprocal Co-IP, anti-Phc2 ChIP at Hox loci, and compound knockout genetic epistasis

    PMID:16024804

    Open questions at the time
    • Direct PHC1 occupancy (versus PHC2) at Hox loci not separately mapped
    • Quantitative contribution of each paralog to repression not partitioned
  12. 2013 High

    Linked PHC1 loss-of-function to primary microcephaly and connected its disease mechanism to loss of H2A ubiquitination, Geminin accumulation, and impaired DNA damage repair.

    Evidence Patient and control cell assays with shRNA/siRNA depletion, H2A ubiquitination and Geminin Western blots, DNA repair assays, and PHC1 rescue

    PMID:23418308

    Open questions at the time
    • The direct enzymatic link from PHC1 to H2A ubiquitination versus an indirect effect not fully dissected
    • How Geminin accumulation leads to microcephaly not mechanistically resolved
  13. 2021 High

    Uncovered a PRC1-independent function whereby PHC1 activates Nanog transcription and stabilizes chromatin architecture at the Nanog locus to maintain pluripotency, distinguishing an activating role from its canonical repressive one.

    Evidence PHC1-Nanog Co-IP, Hi-C, CRISPR/siRNA depletion, Nanog rescue, and luciferase reporter assays

    PMID:33990559

    Open questions at the time
    • How the same protein switches between repressive and architectural/activating modes not defined
    • Whether the Nanog-stabilizing function requires the SAM domain not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PHC1 is targeted to specific loci and how it toggles between canonical PRC1-mediated repression and PRC1-independent chromatin-architectural activation at genes such as Nanog.
  • No structural model of full-length PHC1 within an assembled complex on chromatin
  • Genome-wide PHC1 occupancy map and its determinants not established
  • Mechanistic switch between repressive and activating functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2
Partners
BMI1CBX2NANOGPHC2RING1BSCMH1
Complex memberships
canonical PRC1 (cPRC1)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RAE28 (PHC1), BMI1, and M33 co-immunoprecipitate from mouse embryonic nuclear extracts and exist in large multimeric complexes by gel filtration; RAE28 and BMI1 interact physically but RAE28 and M33 do not interact with each other directly. Different PcG complexes form in different cell types (e.g., RAE28/M33 complex in F9 cells lacking BMI1). Domain mapping localized interaction surfaces. Co-immunoprecipitation from embryonic nuclear extracts, gel filtration chromatography, domain-deletion interaction mapping Biochemical and biophysical research communications Medium 9571155
1998 The SAM (SPM) domain of RAE28 (PHC1) can self-associate in vitro, and also mediates heterologous interaction with the SAM domains of Drosophila Scm and polyhomeotic (ph). Mutagenesis of conserved residues (L33, L41, I62) in ph SAM identified critical interface residues, while W1 and G50 are required for domain structure. In vitro SAM domain binding assays, site-directed mutagenesis of SAM domain residues Developmental genetics High 9499582
1998 GST-RAE28 fusion protein exhibits sequence-specific DNA binding activity in vitro, recognizing consensus sequences including 5'-ACCA-3', 5'-ACCCA-3', 5'-CTATCA-3', and 5'-TGCC-3', as identified by the SELEX method. GST fusion protein pulldown with SELEX (selected and amplified binding site method), sequence analysis of enriched oligonucleotides Biochemistry and molecular biology international Low 9861444
1999 Mouse Scmh1 (mammalian Scm homolog) interacts in vitro with RAE28/mph1 (PHC1) via their SPM domains, analogous to the Drosophila ph-Scm interaction. In vitro protein interaction assay via SPM domain Differentiation; research in biological diversity Medium 10653359
1999 The rae28/mph1 gene promoter contains a pair of inverted differentiation response sequences (DRS) required for transcriptional activation during retinoic acid-mediated F9 cell differentiation; DRS-binding factors were detected by EMSA and DNase I footprinting. Nucleotide substitutions in the 3' DRS abolished factor binding and transcriptional activation. Transient transfection reporter assays, EMSA, DNase I footprinting, site-directed mutagenesis of promoter elements Biochemical and biophysical research communications Medium 10462505
2000 rae28 (PHC1) is required for maintenance (not initiation) of Hoxb3 expression boundaries in the hindbrain and pharyngeal arches; in rae28-deficient mice, Hoxb3 expression initiates normally but becomes ectopically derepressed by E9.5–10.5. Upstream regulators kreisler and Krox20 are unaffected, indicating rae28 acts downstream or in parallel to establish stable repression. In situ hybridization in rae28-knockout mouse embryos, genetic loss-of-function analysis Mechanisms of development Medium 11044623
2001 rae28 (PHC1) is required for the transition from pro-B to pre-B lymphocyte stage in a gene-dosage-dependent manner, as demonstrated by severe B-cell maturation arrest in rae28-/- chimeric mice and impaired IL-7-dependent colony-forming ability in both homozygous and heterozygous lymphocytes. Chimeric mouse reconstitution with GFP-labeled rae28-/- fetal liver cells, in vitro IL-7-dependent colony assay, flow cytometry of B-cell developmental stages Experimental hematology Medium 11164110
2002 rae28 (PHC1) is required for sustaining hematopoietic stem cell (HSC) activity: rae28-/- fetal liver has a 20-fold reduction in competitive repopulating units (CRUs) and 15-fold decreased CRU self-renewal activity, as shown by serial transplantation into lethally irradiated mice. Competitive repopulation assay, serial transplantation in lethally irradiated congenic mice, long-term culture-initiating cell (LTC-IC) assay The Journal of experimental medicine High 11901201
2002 rae28 (PHC1) sustains expression of the cardiac selector gene Nkx2.5 in a maintenance phase after initiation; genetic complementation by NKX2.5 overexpression suppressed cardiac anomalies in rae28-/- embryos, establishing that Nkx2.5 is a downstream effector of rae28 in cardiac morphogenesis. Ubiquitous rae28 re-expression restored Nkx2.5 expression, while cardiomyocyte-specific re-expression did not rescue cardiac defects, indicating rae28 acts through a non-cardiomyocyte pathway. Knockout mouse phenotyping, genetic complementation with NKX2.5 transgene, transgenic rescue with cardiomyocyte-specific vs. ubiquitous rae28 expression The Journal of clinical investigation High 11950896 12122109
2003 Rae28/Ph1 (PHC1) and Ring1B dissociate from chromatin upon chromatin condensation in mitotic prophase in U2-OS cells, and show significant localization changes concordant with chromatin configuration changes during meiotic prophase in mouse oocytes. Dissociation temporally correlates with transcriptional arrest in both mitosis and meiosis. Immunofluorescence with monoclonal antibodies in mitotic somatic cells and meiotic mouse oocytes, live-cell and fixed imaging Histochemistry and cell biology Medium 12883906
2004 rae28 (PHC1) is required for long-term repopulating ability of HSCs: rae28-/- fetal liver cells could initially reconstitute irradiated mice, but showed progressive loss of HSC self-renewal over 12 months (mean stem cell activity reduced to one-tenth of wild-type after 12 months), failure to expand the Lin-c-kit+Sca-1high HSC-enriched subpopulation, and inability to reconstitute secondary recipients. Serial bone marrow transplantation, flow cytometry of HSC-enriched subpopulations, mean stem cell activity (MAS) quantification European journal of haematology High 15245505
2005 Phc1 and Phc2 act synergistically in canonical PRC1 complexes to mediate polycomb repression of Hox cluster genes in anterior-posterior specification; co-immunoprecipitation confirmed physical interaction of their protein products in embryonic extracts, and chromatin immunoprecipitation showed Phc2 binding at Hox loci. Genetic interactions show functional overlap and strict dose-dependence between Phc1 and Phc2. Co-immunoprecipitation from embryonic extracts, chromatin immunoprecipitation (anti-Phc2 monoclonal antibody), compound knockout genetic epistasis (Phc2/Phc1/Rnf110 mutations) Molecular and cellular biology High 16024804
2013 A loss-of-function mutation in PHC1 causes primary microcephaly; the mutation significantly decreases PHC1 protein expression, increases Geminin protein level, and markedly abolishes histone H2A ubiquitination in patient cells. PHC1 depletion in control cells similarly enhances Geminin and decreases H2A ubiquitination. Patient cell defects (H2A ubiquitination, Geminin accumulation, cell cycle defects, and aberrant DNA damage repair) are rescued by PHC1 overexpression. Patient cell functional assays, shRNA/siRNA depletion, ubiquitination assay for histone H2A, Western blotting for Geminin, DNA damage repair assays, rescue by PHC1 overexpression Human molecular genetics High 23418308
2021 PHC1 maintains pluripotency via a PRC1-independent mechanism: PHC1 physically interacts with Nanog, activates Nanog transcription, and stabilizes genome-wide chromatin interactions at the Nanog locus. PHC1 ablation reduces Nanog expression; Nanog overexpression partially rescues pluripotency defects caused by PHC1 depletion. Co-immunoprecipitation (PHC1-Nanog interaction), Hi-C/chromatin conformation capture, CRISPR/siRNA depletion, rescue by Nanog overexpression, luciferase reporter for Nanog transcription Nature communications High 33990559

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. The Journal of experimental medicine 138 11901201
2014 EDR1 physically interacts with MKK4/MKK5 and negatively regulates a MAP kinase cascade to modulate plant innate immunity. PLoS genetics 132 24830651
2005 Mammalian polyhomeotic homologues Phc2 and Phc1 act in synergy to mediate polycomb repression of Hox genes. Molecular and cellular biology 117 16024804
1988 hph-1: a mouse mutant with hereditary hyperphenylalaninemia induced by ethylnitrosourea mutagenesis. Genetics 80 3360305
2013 Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Human molecular genetics 79 23418308
1998 The SAM domain of polyhomeotic, RAE28, and scm mediates specific interactions through conserved residues. Developmental genetics 65 9499582
1998 RAE28, BMI1, and M33 are members of heterogeneous multimeric mammalian Polycomb group complexes. Biochemical and biophysical research communications 65 9571155
1988 Biochemical defect of the hph-1 mouse mutant is a deficiency in GTP-cyclohydrolase activity. Journal of neurochemistry 59 3335865
2012 Uncoupling of eNOS causes superoxide anion production and impairs NO signaling in the cerebral microvessels of hph-1 mice. Journal of neurochemistry 55 22784235
2001 Lack of the Polycomb-group gene rae28 causes maturation arrest at the early B-cell developmental stage. Experimental hematology 50 11164110
2008 Structure basis and unconventional lipid membrane binding properties of the PH-C1 tandem of rho kinases. The Journal of biological chemistry 44 18640982
1996 Tetrahydrobiopterin and biogenic amine metabolism in the hph-1 mouse. Journal of neurochemistry 44 8764604
1988 Hyperphenylalaninemia in the hph-1 mouse mutant. Pediatric research 44 3340448
2003 The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency. Annals of neurology 40 12891653
2002 The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis. The Journal of clinical investigation 39 12122109
1999 A novel member of murine Polycomb-group proteins, Sex comb on midleg homolog protein, is highly conserved, and interacts with RAE28/mph1 in vitro. Differentiation; research in biological diversity 38 10653359
2004 Defective long-term repopulating ability in hematopoietic stem cells lacking the Polycomb-group gene rae28. European journal of haematology 35 15245505
2003 Dissociation of mammalian Polycomb-group proteins, Ring1B and Rae28/Ph1, from the chromatin correlates with configuration changes of the chromatin in mitotic and meiotic prophase. Histochemistry and cell biology 31 12883906
2011 Negative regulation of defence signalling pathways by the EDR1 protein kinase. Molecular plant pathology 30 21726375
2004 Congenic mapping and genotyping of the tetrahydrobiopterin-deficient hph-1 mouse. Molecular genetics and metabolism 24 15234340
2017 Intestinal microbiota as a tetrahydrobiopterin exogenous source in hph-1 mice. Scientific reports 22 28079055
1994 Molecular characterization of HPH-1: a mouse mutant deficient in GTP cyclohydrolase I activity. Biochemical and biophysical research communications 22 7524491
1991 Isolation and characterization of GTP cyclohydrolase I from mouse liver. Comparison of normal and the hph-1 mutant. The Journal of biological chemistry 22 1905717
2013 Impaired behavioural pain responses in hph-1 mice with inherited deficiency in GTP cyclohydrolase 1 in models of inflammatory pain. Molecular pain 21 23421753
2000 Regulation of Hoxb3 expression in the hindbrain and pharyngeal arches by rae28, a member of the mammalian Polycomb group of genes. Mechanisms of development 20 11044623
2023 MITOGEN-ACTIVATED PROTEIN KINASE3 enhances disease resistance of edr1 mutants by phosphorylating MAPKKK5. Plant physiology 19 37638889
2021 PHC1 maintains pluripotency by organizing genome-wide chromatin interactions of the Nanog locus. Nature communications 19 33990559
2011 Differential effects of eNOS uncoupling on conduit and small arteries in GTP-cyclohydrolase I-deficient hph-1 mice. American journal of physiology. Heart and circulatory physiology 19 21963838
1998 Increased inducible nitric oxide synthase protein but limited nitric oxide formation occurs in astrocytes of the hph-1 (tetrahydrobiopterin deficient) mouse. Brain research 19 9729234
2012 PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice. Brain research 18 22982594
1999 Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of tetrahydrobiopterin in the hph-1 mouse. Journal of neurochemistry 16 10582619
2010 Hph1 and Hph2 are novel components of the Sec63/Sec62 posttranslational translocation complex that aid in vacuolar proton ATPase biogenesis. Eukaryotic cell 15 21097665
2007 Tetrahydrobiopterin availability, nitric oxide metabolism and glutathione status in the hph-1 mouse; implications for the pathogenesis and treatment of tetrahydrobiopterin deficiency states. Journal of inherited metabolic disease 15 17242981
2002 Overexpression of Polycomb-group gene rae28 in cardiomyocytes does not complement abnormal cardiac morphogenesis in mice lacking rae28 but causes dilated cardiomyopathy. Laboratory investigation; a journal of technical methods and pathology 12 11950896
1996 Impairment of the nitric oxide/cyclic GMP pathway in cerebellar slices prepared from the hph-1 mouse. Brain research 12 8905183
2014 Infantile hypertrophic pyloric stenosis (IHPS): a study of its pathophysiology utilizing the newborn hph-1 mouse model of the disease. American journal of physiology. Gastrointestinal and liver physiology 10 25359537
2000 Structure and chromosomal localization of the RAE28/HPH1 gene, a human homologue of the polyhomeotic gene. DNA sequence : the journal of DNA sequencing and mapping 7 10902910
1996 Structural organization of the rae28 gene, a putative murine homologue of the Drosophila polyhomeotic gene. Journal of biochemistry 7 8947844
2014 Erythropoietin prevents endothelial dysfunction in GTP-cyclohydrolase I-deficient hph1 mice. Journal of cardiovascular pharmacology 6 25490417
2004 A histological study of the hph-1 mouse mutant: an animal model of phenylketonuria and infantile hypertrophic pyloric stenosis. Anatomia, histologia, embryologia 5 15144277
1999 Linkage analysis of the hph-1 mutation and the GTP cyclohydrolase I structural gene. Molecular genetics and metabolism 5 10479487
2000 Studies on the genotype-phenotype relation in the hph-1 mouse mutant deficient in guanosine triphosphate (GTP) cyclohydrolase I activity. Brain & development 4 10984661
2009 In vivo regulation of phenylalanine hydroxylase in the genetic mutant hph-1 mouse model. Molecular genetics and metabolism 3 19560382
2018 Identification and expression analysis of EDR1-like genes in tobacco (Nicotiana tabacum) in response to Golovinomyces orontii. PeerJ 2 30018863
2005 Cloning, characterization and expression of wheat EDR1 (enhanced disease resistance) gene. Zhi wu sheng li yu fen zi sheng wu xue xue bao = Journal of plant physiology and molecular biology 2 16222089
1999 Characterization of cis-elements required for the transcriptional activation of the rae28/mph1 gene in F9 cells. Biochemical and biophysical research communications 2 10462505
2026 The EDR1-PP2A phospho-regulatory module fine-tunes MYC2-mediated plant disease resistance. The Plant cell 1 41411321
1998 Sequence-specific DNA binding activity in the RAE28 protein, a mouse homologue of the Drosophila polyhomeotic protein. Biochemistry and molecular biology international 1 9861444

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