The Growth-Suppressive Function of the Polycomb Group Protein Polyhomeotic Is Mediated by Polymerization of Its Sterile Alpha Motif (SAM) Domain

Robinson, Angela K.; Leal, Belinda Z.; Chadwell, Linda V.; Wang, Renjing; Ilangovan, Udayar; Kaur, Yogeet; Junco, Sarah E.; Schirf, Virgil; Osmulski, Paweł A.; Gaczyńska, Maria; Hinck, Andrew P.; Demeler, Borries; McEwen, Donald G.; Kim, Chongwoo A.

doi:10.1074/jbc.m111.336115

Cited by 56 publications

(94 citation statements)

References 39 publications

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“…SAM domain-mediated polymerization is therefore an attractive model to explain the propagation of PcG silencing (Kim et al 2002(Kim et al , 2005Peterson et al 2004). From that perspective, Ph, one of the core components of PRC1, may be responsible for the spreading of PRC1 through Ph-SAM polymerization (Robinson et al 2012;Isono et al 2013). The compact chromatin environment formed by PRC1 spreading may improve the enzymatic activity of PRC2 (Yuan et al 2012), and the capacity of the Pc chromodomain to interact with H3K27me3 may also contribute to the synergistic spreading of PcG silencing.…”

Section: Discussionmentioning

confidence: 99%

Sex comb on midleg (Scm) is a functional link between PcG-repressive complexes inDrosophila

et al. 2015

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The Polycomb group (PcG) proteins are key regulators of development in Drosophila and are strongly implicated in human health and disease. How PcG complexes form repressive chromatin domains remains unclear. Using crosslinked affinity purifications of BioTAP-Polycomb (Pc) or BioTAP-Enhancer of zeste [E(z)], we captured all PcG-repressive complex 1 (PRC1) or PRC2 core components and Sex comb on midleg (Scm) as the only protein strongly enriched with both complexes. Although previously not linked to PRC2, we confirmed direct binding of Scm and PRC2 using recombinant protein expression and colocalization of Scm with PRC1, PRC2, and H3K27me3 in embryos and cultured cells using ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing). Furthermore, we found that RNAi knockdown of Scm and overexpression of the dominant-negative Scm-SAM (sterile α motif) domain both affected the binding pattern of E(z) on polytene chromosomes. Aberrant localization of the Scm-SAM domain in long contiguous regions on polytene chromosomes revealed its independent ability to spread on chromatin, consistent with its previously described ability to oligomerize in vitro. Pull-downs of BioTAPScm captured PRC1 and PRC2 and additional repressive complexes, including PhoRC, LINT, and CtBP. We propose that Scm is a key mediator connecting PRC1, PRC2, and transcriptional silencing. Combined with previous structural and genetic analyses, our results strongly suggest that Scm coordinates PcG complexes and polymerizes to produce broad domains of PcG silencing.

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Section: Discussionmentioning

confidence: 99%

Sex comb on midleg (Scm) is a functional link between PcG-repressive complexes inDrosophila

et al. 2015

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“…This result suggests that PC and PH do not solely operate as part of the PRC1 complex, consistent with previous studies (Buchenau et al 1998). The longer residence times observed for PH::GFP may reflect multimerization of PH via the SAM domain, which has been shown to be required for PH-mediated gene silencing (Robinson et al 2012). The cell type-specific differences that we observe in the kinetic behavior of PH::GFP raise the intriguing possibility that some of these may be due to regulation of sterile a motif (SAM) domain polymerization and thus PH silencing properties.…”

Section: Discussionmentioning

confidence: 99%

In vivo Polycomb kinetics and mitotic chromatin binding distinguish stem cells from differentiated cells

Fonseca

Steffen²,

Müller³

et al. 2012

Genes Dev.

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Epigenetic memory mediated by Polycomb group (PcG) proteins must be maintained during cell division, but must also be flexible to allow cell fate transitions. Here we quantify dynamic chromatin-binding properties of PH::GFP and PC::GFP in living Drosophila in two cell types that undergo defined differentiation and mitosis events. Quantitative fluorescence recovery after photobleaching (FRAP) analysis demonstrates that PcG binding has a higher plasticity in stem cells than in more determined cells and identifies a fraction of PcG proteins that binds mitotic chromatin with up to 300-fold longer residence times than in interphase. Mathematical modeling examines which parameters best distinguish stem cells from differentiated cells. We identify phosphorylation of histone H3 at Ser 28 as a potential mechanism governing the extent and rate of mitotic PC dissociation in different lineages. We propose that regulation of the kinetic properties of PcG-chromatin binding is an essential factor in the choice between stability and flexibility in the establishment of cell identities.

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“…Mutation of a single amino acid in the SAM domain, which blocks polymerization, ruins the repressor capabilities of PH protein [76]. SAM domain polymerization is essential for the in vivo growth suppressive function of PH too [77]. SAM motif was also found in dSFMBT protein (Table 1).…”

Section: Evolutionarily Conserved Domains In Pcg Proteinsmentioning

confidence: 99%

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

2018

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Originally two types of Polycomb Repressive Complexes (PRCs) were described, canonical PRC1 (cPRC1) and PRC2. Recently, a versatile set of complexes were identified and brought up several dilemmas in PRC mediated repression. These new class of complexes were named as non-canonical PRC1s (ncPRC1s). Both cPRC1s and ncPRC1s contain Ring finger protein (RING1, RNF2) and Polycomb group ring finger catalytic (PCGF) core, but in ncPRCs, RING and YY1 binding protein (RYBP), or YY1 associated factor 2 (YAF2), replaces the Chromobox (CBX) and Polyhomeotic (PHC) subunits found in cPRC1s. Additionally, ncPRC1 subunits can associate with versatile accessory proteins, which determine their functional specificity. Homozygous null mutations of the ncPRC members in mice are often lethal or cause infertility, which underlines their essential functions in mammalian development. In this review, we summarize the mouse knockout phenotypes of subunits of the six major ncPRCs. We highlight several aspects of their discovery from fly to mice and emerging role in target recognition, embryogenesis and cell-fate decision making. We gathered data from stem cell mediated in vitro differentiation assays and genetically engineered mouse models. Accumulating evidence suggests that ncPRC1s play profound role in mammalian embryogenesis by regulating gene expression during lineage specification of pluripotent stem cells.

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The Growth-Suppressive Function of the Polycomb Group Protein Polyhomeotic Is Mediated by Polymerization of Its Sterile Alpha Motif (SAM) Domain

Cited by 56 publications

References 39 publications

Sex comb on midleg (Scm) is a functional link between PcG-repressive complexes inDrosophila

Sex comb on midleg (Scm) is a functional link between PcG-repressive complexes inDrosophila

In vivo Polycomb kinetics and mitotic chromatin binding distinguish stem cells from differentiated cells

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

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