nemhcirnedezamroNnemhcirnedezilAt Bt CiBamroNnoUdritaroprocnOur laboratory, the Developmental Genetics Laboratory, focuses on the Early S (Rnf20cKO)Late S (Rnf20cKO)il39BrdUincorporation in S1WTRnf20cKOWTRnf20cKO-50 KbStart End +50 Kb-50 KbStart End +50 KbMeta S1-RRMeta S4-RREarly S (WT)Late S (WT)E-RRL-RRMeta S1-RRH2Bub ChIP-seq1.61.20.80.4-5 KbTSSH2Bub High GenesUntreatedTriptolide, 1uM (8h)iCdk9 I, 1 uM(8h)iCdk9 II, 1 uM(8h)Meta geneTTS+5 Kbrole of epigenetic regulation in organ development. Our recent research focuses on DNA replication of the mammalian genome. The mammalian ge-nome is approximately 1000-times larger than the typical prokaryotic genome. To facilitate efficient replication of mammalian DNA, some regions of the genome replicate early while others replicate late in S-phase, a process that is known as replication timing. We have found that mono-ubiquitination of his-tone H2B lysine 120 (H2BK120ub) plays a role in regulating replication timing in mammalian cells (Figure 1A). RNF20, an E3 ubiquitin ligase, interacts with RNA polymerase II (RNAP2) during transcriptional elongation and deposits H2BK120ub (Figure 1B, 1C). H2BK120ub-enriched regions replicate early in S-phase. By regulating DNA replication, H2BK120ub may thus play a role in organ development and in regulation of immune functions.A part of our laboratory is committed to the maintenance of a high-standard mouse facility in IMS. Through this Core Animal Facility, our group generates knock-out and transgenic animals for the various research laboratories in IMS. We also provide germ-free, gnotobiotic and humanized mice to IMS research-ers.We are also engaged in the generation of human iPSC-derived NKT (iPS-NKT) cells, with the goal of future clinical use of these cells in cancer therapy. We have started a Phase I clinical study to evaluate the safety of iPS-NKT cells in October 2020. The Core Facility for iPSC Research is developing a protocol with shorter cell culture times and higher efficiency of NKT induction and pro-duction from human iPSCs. This will help to facilitate a robust supply of NKT cells for more patients in the future. This research is mainly supported by the Agency for Medical Research and Development (AMED).Figure: Regulation of mammalian replication timing by H2BK120ubA, The bottom panel shows a screenshot of genomic regions that are undergoing DNA replication in early or late S-phase. The y-axis shows the level of DNA replica-tion measured by BrdU incorporation. The top panel shows that the early replicating regions are affected by the loss of RNF20, and thereby H2BK120ub, while the late replicating regions are not. B, H2BK120ub is depos-ited over the gene body in WT cells (green). However, suppression of Pol2 activity by the selective Pol2 inhibi-tor triptolide (red), or inhibition of the CDK9 kinase that is essential for Pol2 elongation (blue and pink, two types of inhibitors), leads to loss of H2BK120ub. C, Working model showing Pol2-dependent recruitment of RNF20 and downstream H2BK120ub deposition in the gene body.Recent Major PublicationsEto H, Kishi Y, Yakushiji-Kaminatsui N, Sugishita H, Utsunomiya S, Koseki H, Gotoh Y. The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon. Nat Commun 11, 5709 (2020)Healy E, Mucha M, Glancy E, Fitzpatrick DJ, Conway E, Neikes HK, Monger C, Van Mierlo G, Baltissen MP, Koseki Y, Vermeulen M, Koseki H, Bracken AP*. PRC2.1 and PRC2.2 Synergize to Coordinate H3K27 Trimethylation. Mol Cell 76, 437-452.e6 (2019)Fursova NA, Blackledge NP, Nakayama M, Ito S, Koseki Y, Farcas AM, King HW, Koseki H, Klose RJ. Synergy between Variant PRC1 Complexes Defines Polycomb-Mediated Gene Repression. Mol Cell 74, 1-17 (2019)Invited presentationsKoseki H. “Polycomb in haematipoietic differentiation” The Chromatin and Epigenetics biweekly virtual seminar series, Tsinghua University (Online) December 2020Koseki H. “Daten als Basis der medizinischen Forschung für eine personalisierte Medizin: Das Mikrobiom und das Metabolom, die Treiber von entzündlichen Erkrankun-gen und Krebsleiden” KOOPERATIONSVERANSTALTUNG BADEN-WÜRTTEMBERG – KANAGAWA (Japan/Online) November 2020Laboratory for Developmental GeneticsTeam Leader: Haruhiko Koseki
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