Neurosurgery notes/Tumours/Tumour genetics/Epigenetics/Polycomb repressive complexes (PRCs)

Polycomb repressive complexes (PRCs)

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Epigenetics

General

  • Molecular complexes involved in histone modification processes

Main function

  • Recruited to target sites by multiple mechanisms, including the
    • Binding of hypomethylated CpG islands
    • Specific interaction with transcription factors and long ncRNAs
    • Recognition of chromatin marks deposited by other histone-modifying complexes
      • Through a coordinated action between PRC1 and PRC2:
        • PRC2-dependent H3K27me3 mark increases affinity and recruits CBX-containing cPRC1
        • KDM2B-mediated recruitment to nonmethylated CpG islands of ncPRC1 drives H2AK119ub that conversely promotes binding of PRC2

Classified into two types:

PRC1

  • Function: adds an ubiquitin moiety to histone H2A at Lys119 (H2AK119ub1),
  • Core protein subunits consisting of a
    • RING1 protein (either RING1A or RING1B), which is an E3-ubiquitin ligase that adds an ubiquitin group to histone H2A at Lysine 119
      • Based on the cofactor that binds to the RING1 subunit, PRC1 complexes are often divided into
        • Canonical PRC1 complexes (cPRC1)
          • Are assembled around PCGF2/4 and contain one chromobox protein (CBX2, 4, 6–8) that is able to recognize and bind the H3K27me3 histone mark implemented by the PRC2 complex
        • Noncanonical PRC1 complexes (ncPRC1)
          • Bind to the RYBP (RING1 and YY1-binding protein ) or its paralog YAF2 and associate with
            • PCGF1 → PRC1.1 (BCOR is a subunit of PRC1.1)
                • PRC1.1 subunits
                Principal interactions
                Functional notes
                BCOR
                PCGF1, KDM2B, BCL6, MLLT3, IRF8
                PRC1.1 core protein. It seems able to bind AF9, a protein associated with SEC complex, but the relevance of this interaction has not been determined
                BCORL1
                PCGF1, KDM2B, CTBP1, HDACs
                PRC1.1 core protein, alternatively to BCoR. It does not bind BCL-6, but the transcriptional corepressor CTBP1. Interacts with different Class II HDACs
                PCGF1
                BCOR, KDM2B, RYBP, YAF2
                PRC1.1 core protein
                KDM2B
                BCOR, PCGF1, SKP1, unmethylated CpG islands
                PRC1.1 core protein. It demethylates H3K36me3/me2. It can participate in the formation of the SCF complex
                RING1a/RING1b
                PCGF1, RYBP, YAF2, CBX8
                Canonical and noncanonical PRC1s core protein. It ubiquitinates H2AK119
                UBP7
                BCOR, PCGF1, CBX8, RING1a/b, PCGF2/MEL18, PCGF4/BMI1, PTEN, MDM2, P53, DMNT
                De-ubiquitinating action. It can be associated with other noncanonical PRC1 as well as the classic PRC1
                SKP1
                KDM2B, other SCF proteins
                Ubiquitinating action. It binds KDM2B. It participates in the formation of the SCF complex
                RYBP/YAF2
                PGGF1, RING1b, YY1
                They may link PRCs to YY1
                Associated proteins
                Principal interactions
                Functional notes
                YY1
                RYBP, YAF2, DNA, INO80 complex, P53, HDACs
                Transcription factor. The real relevance in the in vivo PRCs recruitment is not yet determined
                CBX8
                RING1a/b, H3K27me3, PCGF1/2/3/5/6, PHC1/2, MLLT1
                It recruits the PRCs that contain it at H3K27me3 histones, establishing a functional cross-link with the PRC2s. Not present in PRC1.1
                BCL6
                BCOR, NCOR1, SMRT, HDACs, NuRD, MET3, DNA
                Transcription factor. It recruits PRC1.1 by link with BCOR. It also has PRC independent activity: it is able to bind other proteins involved in gene silencing
                Schematic representation of the polycomb repressive complex 1.1 model. The core complex is composed of the catalytic enzyme RING1A/B that forms a dimer with PCGF1 through the RING finger domains, and that deposits an ubiquitin moiety to histone H2A at Lys119 (H2AK119ub). BCOR binds to PCGF1 by means of its PUFD domain, while RYBP is bound to the RAWUL domain of RING1A/B. Recruitment to chromatin is due to KDM2B that recognizes nonmethylated CpG islands by its CXXC-binding domain. Other members of the complex are SKP1, that associates with KDM2B, and USP7, acting as a deubiquitinating enzyme. PUFD: PCGF Ub-like fold discriminator.
                Schematic representation of the polycomb repressive complex 1.1 model. The core complex is composed of the catalytic enzyme RING1A/B that forms a dimer with PCGF1 through the RING finger domains, and that deposits an ubiquitin moiety to histone H2A at Lys119 (H2AK119ub). BCOR binds to PCGF1 by means of its PUFD domain, while RYBP is bound to the RAWUL domain of RING1A/B. Recruitment to chromatin is due to KDM2B that recognizes nonmethylated CpG islands by its CXXC-binding domain. Other members of the complex are SKP1, that associates with KDM2B, and USP7, acting as a deubiquitinating enzyme. PUFD: PCGF Ub-like fold discriminator.
            • PCGF3/5 → PRC1.3/1.5
            • PCGF6 → PRC1.6
          • RYBP and YAF2 play a fundamental role in stimulating E3 ligase activity of PRC1 and enhancing H2AK119ub deposition
          • Importantly, RYBP and YAF2 lack the capacity to bind to H3K27me3 and can be recruited to chromatin in cells lacking functional PRC2.
        • ‘Variant’
    • PCGF protein (PCGF 1–6)
      • Different PRC1 complexes are defined by the different PCGF protein that associates to the complex and directs interaction with distinct auxiliary proteins, giving rise to PRC1 complexes with differential target specificity and chromatin recruitment patterns

PRC2

  • Function: catalyses the addition of one to three methyl groups to histone H3 at Lys27, leading to H3K27me1, H3K27me2 or H3K27me3
  • Core protein subunits of PRC2 complex are
      • Suz12 (with a Zinc finger domain)
      • Eed (with a WD repeat domain that recognizes trimethylated peptides)
      • Ezh2 (the SET-domain containing catalytic subunit)
      notion image
  • Silent a wide range of genes including HOX group genes