Polycomb group (PcG) factors are maintenance repressors for developmen-PRC2RepressionPRC1.1TranscriptionActivation39UbSUZ12H2AK119ub1H3K27me3Unmethylated CpGProteasomeEZH1/2EEDRING1PCGF1UbBCORSKP1AKDM2BCpG islandsDevelopmental signals-Activated enhancers?-PTMs of PCGF1-PRC1?SUZ12RING1PCGF1BCORSKP1AKDM2BProteasomeCpG islandsPRC2UbEZH1/2UbEEDUbUbPRC1.1tal genes but are also involved in target gene activation though unknown mechanisms. Variant PRC1 that associates with PCGF1 (PCGF1-PRC1) initi-ates PcG repression by recognizing CpG islands (CGIs) by KDM2B and medi-ates histone H2A mono-ubiquitination at K119 (H2AK119ub1) by RING1 pro-teins. Aside from H2AK119ub1, PCGF1-PRC1 associates with SKP1A, another E3 ligase module that is linked with ubiquitin-proteasome the system (UPS). However, the molecular relevance of PCGF1-PRC1 to UPS remains unclear.To investigate the link between PCGF1-PRC1 and the proteasome, we per-formed PCGF1-PRC1 proteomics and identified multiple components of the proteasome. Furthermore, we developed a method to specifically isolate polyu-biquitylated proteins from cell lysates using Tandem Ubiquitin Binding Entities (TUBEs). We found that SKP1A can generate polyubiquitylated proteins whose function was greatly attenuated in SKP1A-knockout ESCs. LC-MS/MS analysis identified EED, a PRC2 component, as a SKP1A substrate.To provide biological relevance to SKP1A-mediated degradation of EED, we performed ES-cell differentiation and investigated the relationship between the transcriptome and the dynamics of chromatin occupancy by EED. As a result, we found that SKP1A is involved in eviction of EED via UPS from CGIs to activate PcG-mediated repressed genes. This study therefore reveals a previ-ously unappreciated regulatory process for SKP1A-mediated protein turnover that may contribute to spatiotemporally regulated expression of developmental genes on chromatin.Figure: Schematic summary of the role for SKP1A in disrupting PCGF1–PRC1-initiated gene silencingPCGF1-PRC1 contributes to the silencing of CGI-associat-ed genes by bringing PRC2 to the CGIs via H2AK119ub1. Upon activation of the SKP1A subunit of PCGF1-PRC1, likely upon receipt of developmental signals, SKP1A triggers polyubiquitination of EED and facilitates the eviction of PRC2 from target genes via the UPS and con-comitant activation.Recent Major PublicationsSekita A, Kawasaki H, Fukushima-Nomura A, Yashiro K, Tanese K, Toshima S, Ashizaki K, Miyai T, Yazaki J, Kobayashi A, Namba S, Naito T, Wang QS, Kawakami E, Seita J, Ohara O, Sakurada K, Okada Y, Amagai M, Koseki H. Multifaceted analysis of cross-tissue transcriptomes reveals phenotype-endotype associations in atopic der-matitis. Nat Commun 14, 6133 (2023)Koseki H, Sharif J. Editorial overview: Epigenetic inheri-tance: A shortcut to environmental adaptation? Curr Opin Genet Dev 82, 102094 (2023)Masui O, Corbel C, Nagao K, Endo T, Kezuka F, Diaban-gouaya P, Nakayama M, Kumon M, Koseki Y, Obuse C, Koseki H*, Heard E*. Polycomb complexes PRC1 and PRC2 are each essential for maintenance of X inactiva-tion in extraembryonic lineages. Nat Cell Biol 25, 134-144 (2023)Invited presentationsKoseki H. “Regeneration of natural killer T (NKT) cells: application of iPSC technology for NKT cell-targeted tumor immunotherapy” Swiss Cancer Center Léman (Lausanne, Switzerland) November 2023Koseki H. “SKP1A links Polycomb-repressed genes with proteasome” EMBL Conference Chromatin and epi-genetics (Heidelberg, Germany) May 2023Koseki H. “SKP1A links Polycomb-repressed genes with proteasome” Cambridge epigenetics club (University of Cambridge) (Cambridge, UK) May 2023Koseki H. “SKP1A links Polycomb-repressed genes with proteasome” University of Oxford (Oxford, UK) May 2023Koseki H. “SKP1A links Polycomb-repressed genes with proteasome” Trinity College Dublin (Dublin, Ireland) May 2023Laboratory for Developmental GeneticsTeam Leader: Haruhiko Koseki
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