Proper transcriptional regulation is critical for the life cycle of multicel-42lular organisms. We study a group of repressive chromatin regulatory factors, namely Polycomb group (PcG), that predominantly contributes to transcriptional control of development/differentiation-related genes. Although it is widely accepted that PcG factors primarily contribute to maintain the re-pressive state of developmental gene expression, our previous studies revealed its impacts on the transition of transcriptional status of target genes that as-sociates with developmental processes. To explore how PcG factors contribute to this transcriptional phase shift, we focused on variant Polycomb repressive complex-1 incorporating PCGF1 (PCGF1-PRC1), which is known to medi-ate mono-ubiquitination of Lysine 119 of Histone H2A (H2AK119ub1) by the RING1B component. Importantly, PCGF1-PRC1 includes another E3 ubiquitin ligase, SKP1A, via its interaction with F-box of KDM2B. Although SKP1A is known to regulate stability of target proteins, its role in PCGF1-PRC1 has not been elucidated. SKP1A was found to associate with CpG islands (CGIs) in a KDM2B-dependent manner in embryonic stem cells (ESCs) but not to contrib-ute to stable down-regulation of PcG-target genes in ESCs. Instead, PcG-target genes, which are upregulated during ESC-to-embryoid body (EB) differentia-tion, were found to require SKP1A for their upregulation. We indeed observed that PcG factors failed to be evicted from these target genes during ESC-to-EB differentiation, suggesting a role of SKP1A to strip PcG factors off the tar-get genes, likely by linking PcG-bound CGIs with the proteasome. This issue was further tested during midbrain development, which accompanies PcG-dependent activation of several PcG-target genes including Meis2. We observed that Meis2 activation required SKP1A-dependent eviction of PcG factors from Meis2-associated CGI. In this work, we propose the role of SKP1A for tran-scriptional activation of PcG-repressed genes.Figure: The role of SKP1A to activate Polycomb-repressed genesA schematic representation of dynamic changes in PcG association with the Meis2 gene during midbrain devel-opment. In 9.0 dpc midbrain, in which Meis2 is silenced, PcG factors bind to promoter and RBS (RING1B-binding site) and facilitate their association. During 9.0 to 9.5 dpc, the midbrain enhancer region is recruited to pro-moter/RBS regions in a PcG-dependent manner. In 9.5 dpc midbrain, SKP1A facilitates dissociation of PcG fac-tors and RBS from the Meis2 promoter in proteasome-dependent manner. This does not occur in the absence of SKP1A (red X).Recent Major PublicationsOhinata Y, Endo TA, Sugishita H, Watanabe T, Iizuka Y, Kawamoto Y, Saraya A, Kumon M, Koseki Y, Kondo T, Ohara O, Koseki H. Establishment of mouse stem cells that can recapitulate the developmental potential of primitive endoderm. Science 4;375(6580):574-578 (2022)Takada Y, Yaman-Deveci R, Shirakawa T, Sharif J, To-mizawa SI, Miura F, Ito T, Ono M, Nakajima K, Koseki Y, Shiotani F, Ishiguro KI, Ohbo K, Koseki H. Maintenance DNA methylation in pre-meiotic germ cells regulates meiotic prophase by facilitating homologous chromo-some pairing. Development 148, dev194605 (2021)Sugishita H, Kondo T, Ito S, Nakayama M, Yakushiji-Kaminatsui N, Kawakami E, Koseki Y, Ohinata Y, Sharif J, Harachi M, Blackledge NP, Klose RJ, Koseki H. Variant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes. Nat Commun 12, 5341 (2021)Invited presentationsKoseki H. “Adoptive iPS-NKT immunotherapy for cancer” The 18th Annual Meeting of the Society for Reconstruc-tion and Regeneration in Urologic Surgery (Online) June 2021Laboratory for Developmental GeneticsTeam Leader: Haruhiko Koseki
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