Laboratory for Developmental Epigenetics | RIKEN BDR

Laboratory for Developmental Epigenetics

Team Leader

Ichiro HirataniPh.D.

Photo of principal investigator

  • Location:Kobe / Developmental Biology Buildings
  • E-mail:ichiro.hiratani[at]riken.jpPlease replace [at] with @.
  • Lab Website

Research Summary

We wish to clarify the molecular mechanisms underlying global facultative heterochromatin formation during early mouse embryogenesis, with the belief that understanding the developmental regulation of higher-order chromosome organization will lead to a deeper understanding of cell differentiation.
The term facultative heterochromatin refers to chromosomal regions that condense, become inactivated, and are stably maintained in this manner after a certain developmental stage. A classic example is the inactive X chromosome in mammals, which becomes detectable immediately prior to the formation of germ layers and is stably maintained thereafter in all downstream lineages. Intriguingly, we recently discovered that many autosomal domains also undergo a similar process of facultative heterochromatin formation at the same developmental stage, which accounts for more than 6% of the genome. This suggests that facultative heterochromatin formation at this stage is not specific to the inactive X, but is rather a more widespread phenomenon affecting the entire genome. Recent studies have also revealed low reprogramming efficiency of cells immediately after this developmental stage, already as low as downstream somatic cell types. Thus, this facultative heterochromatin is a common epigenetic feature of all somatic cells beyond the germ layer formation stage, and the reprogramming experiments imply a potential link to the cell's differentiated state.
For these reasons, we combine genome-wide approaches with molecular and cell biology and imaging techniques to elucidate the molecular mechanisms underlying the facultative heterochromatin formation process. In the future, we will address the biological significance of this phenomenon and eventually wish to understand the fundamental implications of higher-order chromosome organization.

Early- and late-replicating DNA localize to the interior (green) and periphery (red) of the nucleus, respectively. Because of this relationship, genome-wide DNA replication profiling (graphs) can be used to deduce the 3D genome organization at the sequence level.

Genome-wide DNA replication profiling during ES cell differentiation can reveal domains that show large-scale changes in nuclear organization.

Electron microscopy reveals a large-scale genome reorganization during pre- (left) to post-epiblast (right) transition, consistent with predictions made by DNA replication profiling.

Research Theme

  • 3D genome organization changes during cell differentiation
  • Regulatory mechanisms of 3D genome organization
  • Development of a single-cell genome-wide DNA replication profiling technology

Main Publications List

  • Miura H, Takahashi S, Shibata T, et al.
    Mapping replication timing domains genome wide in single mammalian cells with single-cell DNA replication sequencing.
    Nature Protocols (2020) doi: 10.1038/s41596-020-0378-5
  • Abdalla MOA, Yamamoto T, Maehara K, et al.
    The Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis.
    Nature Communications 10, 3778 (2019) doi: 10.1038/s41467-019-11378-4
  • Miura H, Takahashi S, Poonperm R, et al.
    Single-cell DNA replication profiling identifies spatiotemporal developmental dynamics of chromosome organization
    Nature Genetics (2019) doi: 10.1038/s41588-019-0474-z
  • Takahashi S, Miura H, Shibata T, et al.
    Genome-wide stability of the DNA replication program in single mammalian cells.
    Nature Genetics (2019) doi: 10.1038/s41588-019-0347-5
  • Takahashi S, Kobayashi S and Hiratani I.
    Epigenetic differences between naïve and primed pluripotent stem cells.
    Cellular and Molecular Life Sciences 75(7). 1191–1203 (2017) doi :10.1007/s00018-017-2703-x
  • Shang WH, Hori T, Martins N MC, et al.
    Chromosome engineering allows the efficient isolation of vertebrate neocentromeres. Developmental Cell 24. 635–648 (2013) doi: 10.1016/j.devcel.2013.02.009
  • Ryba T, Battaglia D, Pope B D, et al.
    Genome-scale analysis of replication timing: from bench to bioinformatics.
    Nature Protocols 6. 870–895 (2011) doi:10.1038/nprot.2011.328
  • Hiratani I and Gilbert D M.
    Autosomal lyonization of replication domains during early mammalian development.
    Advances in Experimental Medicine Biology 695. 41–58 (2010) doi:10.1007/978-1-4419-7037-4_4
  • Ryba T, Hiratani I, Lu J, et al.
    Evolutionarily conserved replication timing profiles predict long-range chromatin interactions and distinguish closely related cell types.
    Genome Research 20. 761–770 (2010) doi:10.1101/gr.099655.109
  • Hiratani I, Ryba T, Itoh M, et al.
    Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis.
    Genome Research 20.155–169 (2010) doi:10.1101/gr.099796.109