RIKEN Center for Integrative Medical Sciences Laboratory for Developmental Genetics

Team Leader: Haruhiko Koseki (M.D., Ph.D)

Japanese Page

Research Summary

The Developmental Genetics Research Group studies epigenetic regulation of organ development and stem cell functions, mediated by Polycomb group (PcG) proteins and DNA methylation (5mC) mechanisms.
We showed that PcG proteins bind unmethylated CpG dinucleotides via the CxxC domain of KDM2B, which is a component of the non-canonical polycomb repressive complex 1 (ncPRC1). This promotes deposition of H3K27me3 by the polycomb repressive complex 2 (PRC2), and subsequent recruitment of the canonical PRC1 (cPRC1)- leading to transcriptional silencing. We aim to uncover the factors that regulate: (1) ncPRC1 recruitment to unmethylated CpGs, and, (2) cPRC1 recruitment downstream of PRC2.
Methylated CpGs, that are not bound by PcG proteins, are substrates of DNA methylation machinery. We previously discovered that DNA methylation is faithfully maintained by the combined role of DNMT1 and NP95/UHRF1. We are now elucidating novel molecules that function upstream of NP95-DNMT1, and couple DNA replication with maintenance methylation in mammalian cells.
Our group also focuses on the broad link between epigenetic factors and DNA replication. We have identified previously unknown epigenetic factors that specifically regulate replication timing in the euchromatin compartment of the genome in the S-phase.
Finally, our group is responsible to operate the animal facility affiliated to Yokohama Institute that includes cryopreservation and generation of genetic resources and human iPS cell facility.

Main Research Fields

Biology

Related Research Fields

Medicine, Dentistry & Pharmacy

Keywords

Epigenetics
Disease model
iPS cells

Selected Publications

1.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)
2.Yakushiji-Kaminatsui N, Kondo T, Hironaka KI, Sharif J, Endo TA, Nakayama M, Masui O, Koseki Y, Kondo K, Ohara O, Vidal M, Morishita Y, Koseki H.:
"Variant PRC1 competes with retinoic acid-related signals to repress Meis2 in the mouse distal forelimb bud."
Development 145. pii: dev166348. doi: 10.1242/dev.166348(2018)
3.Conway E, Jerman E, Healy E, Ito S, Holoch D, Oliviero G, Deevy O, Glancy E, Fitzpatrick DJ, Mucha M, Watson A, Rice AM, Chammas P, Huang C, Pratt-Kelly I, Koseki Y, Nakayama M, Ishikura T, Streubel G, Wynne K, Hokamp K1, McLysaght A, Ciferri C, Di Croce L, Cagney G, Margueron R, Koseki H, Bracken AP.:
"A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities."
Mol Cell. 70, 408-421.e8.(2018)
4.Almeida M, Pintacuda G, Masui O, Koseki Y, Gdula M, Cerase A, Brown D, Mould A, Innocent C, Nakayama M, Schermelleh L, Nesterova TB, Koseki H, Brockdorff N.:
"PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation."
Science 356, 1081-1084 (2017)
5.Dong Y, Isono KI, Ohbo K, Endo TA, Ohara O, Maekawa M, Toyama Y, Ito C, Toshimori K, Helin K, Ogonuki N, Inoue K, Ogura A, Yamagata K, Kitabayashi I, Koseki H.:
"EPC1/TIP60-Mediated Histone Acetylation Facilitates Spermiogenesis in Mice."
Mol Cell Biol, 37: e00082-17(2017)
6.Endoh M, Endo TA, Shinga J, Hayashi K, Farcas A, Ma KW, Ito S, Sharif J, Endoh T, Onaga N, Nakayama M, Ishikura T, Masui O, Kessler BM, Suda T, Ohara O, Okuda A, Klose RJ, Koseki H.:
"PCGF6-PRC1 suppresses premature differentiation of mouse embryonic stem cells by regulating germ cell-related genes."
Elife 6, pii: e21064 (2017)
7.Yamada D, Iyoda T, Vizcardo R, Shimizu K, Sato Y, Endo TA, Kitahara G, Okoshi M, Kobayashi M, Sakurai M, Ohara O, Taniguchi M, Koseki H, Fujii SI.:
"Efficient regeneration of Human Vα24+ invariant NKT cells and their anti-tumor activity in vivo."
Stem Cells 34, 2852-60 (2016)
8.Sharif J, Endo TA, Nakayama M, Karimi MM, Shimada M, Katsuyama K, Goyal P, Brind’Amour J, Sun M-A, Sun Z, Ishikura T, Mizutani-Koseki Y, Ohara O, Shinkai Y, Nakanishi M, Xie H, Lorincz MC, Koseki H.:
"Activation of Endogenous Retroviruses in Dnmt1^-/- ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA."
Cell Stem Cell 19, 81-94 (2016)
9.Yakushiji-Kaminatsui N, Kondo T, Endo TA, Koseki Y, Kondo K, Ohara O, Vidal M, Koseki H.:
"RING1 proteins contribute to early proximal-distal specification of the forelimb bud by restricting Meis2 expression."
Development 143, 276-85 (2016).
10.Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LL, Ito S, Cooper S, Kondo K, Koseki Y, Ishikura T, Long HK, Sheahan TW, Brockdorff N, Kessler BM, Koseki H, Klose RJ.:
"Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation."
Cell 157, 1445-1459 (2014).