RIKEN Center for Integrative Medical Sciences Laboratory for Developmental Genetics

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

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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. Sekita 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 dermatitis."
Nat Commun 14(1):6133 (2023)
2. Masui O, Corbel C, Nagao K, Endo TA, Kezuka F, Diabangouaya P, Nakayama M, Kumon M, Koseki Y, Obuse C, Koseki H, Heard E.:
"Polycomb repressive complexes 1 and 2 are each essential for maintenance of X inactivation in extra-embryonic lineages."
Nat Cell Biol 25(1):134-144 (2023)
3. Takano J, Ito S, Dong Y, Sharif J, Nakajima-Takagi Y, Umeyama T, Han YW, Isono K, Kondo T, Iizuka Y, Miyai T, Koseki Y, Ikegaya M, Sakihara M, Nakayama M, Ohara O, Hasegawa Y, Hashimoto K, Arner E, Klose RJ, Iwama A, Koseki H, Ikawa T.:
"PCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment."
Nat Commun 13(1):7159 (2022)
4. Ohinata 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 375(6580):574-578 (2022)
5. 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(1):5341 (2021)
6. Takada Y, Yaman-Deveci R, Shirakawa T, Sharif J, Tomizawa 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 chromosome pairing."
Development 148(10) (2021)
7. Mei H, Kozuka C, Hayashi R, Kumon M, Koseki H, Inoue A.:
"H2AK119ub1 guides maternal inheritance and zygotic deposition of H3K27me3 in mouse embryos."
Nat Genet 53(4):539-550 (2021)
8. Narita T, Ito S, Higashijima Y, Chu WK, Neumann K, Walter J, Satpathy S, Liebner T, Hamilton WB, Maskey E, Prus G, Shibata M, Iesmantavicius V, Brickman JM, Anastassiadis K, Koseki H, Choudhary C.:
"Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release."
Mol Cell 81(10):2166-2182.e6 (2021)
9. 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(3):437-452.e6 (2019)
10. 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(5):1020-1036.e8 (2019)