Bio

Professional Education


  • Bachelor of Science, Unlisted School (2004)
  • Doctor of Philosophy, Kanazawa University (2010)

Stanford Advisors


Publications

All Publications


  • SCML2 Establishes the Male Germline Epigenome through Regulation of Histone H2A Ubiquitination DEVELOPMENTAL CELL Hasegawa, K., Sin, H., Maezawa, S., Broering, T. J., Kartashov, A. V., Alavattam, K. G., Ichijima, Y., Zhang, F., Bacon, W. C., Greis, K. D., Andreassen, P. R., Barski, A., Namekawa, S. H. 2015; 32 (5): 574-588

    Abstract

    Gametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells.

    View details for DOI 10.1016/j.devcel.2015.01.014

    View details for Web of Science ID 000350989300007

    View details for PubMedID 25703348

  • Poised chromatin and bivalent domains facilitate the mitosis-to-meiosis transition in the male germline. BMC biology Sin, H., Kartashov, A. V., Hasegawa, K., Barski, A., Namekawa, S. H. 2015; 13: 53-?

    Abstract

    The male germline transcriptome changes dramatically during the mitosis-to-meiosis transition to activate late spermatogenesis genes and to transiently suppress genes commonly expressed in somatic lineages and spermatogenesis progenitor cells, termed somatic/progenitor genes.These changes reflect epigenetic regulation. Induction of late spermatogenesis genes during spermatogenesis is facilitated by poised chromatin established in the stem cell phases of spermatogonia, whereas silencing of somatic/progenitor genes during meiosis and postmeiosis is associated with formation of bivalent domains which also allows the recovery of the somatic/progenitor program after fertilization. Importantly, during spermatogenesis mechanisms of epigenetic regulation on sex chromosomes are different from autosomes: X-linked somatic/progenitor genes are suppressed by meiotic sex chromosome inactivation without deposition of H3K27me3.Our results suggest that bivalent H3K27me3 and H3K4me2/3 domains are not limited to developmental promoters (which maintain bivalent domains that are silent throughout the reproductive cycle), but also underlie reversible silencing of somatic/progenitor genes during the mitosis-to-meiosis transition in late spermatogenesis.

    View details for DOI 10.1186/s12915-015-0159-8

    View details for PubMedID 26198001

  • The great escape Active genes on inactive sex chromosomes and their evolutionary implications EPIGENETICS Sin, H., Namekawa, S. H. 2013; 8 (9): 887-892

    Abstract

    Epigenetic mechanisms precisely regulate sex chromosome inactivation as well as genes that escape the silencing process. In male germ cells, DNA damage response factor RNF8 establishes active epigenetic modifications on the silent sex chromosomes during meiosis, and activates escape genes during a state of sex chromosome-wide silencing in postmeiotic spermatids. During the course of evolution, the gene content of escape genes in postmeiotic spermatids recently diverged on the sex chromosomes. This evolutionary feature mirrors the epigenetic processes of sex chromosomes in germ cells. In this article, we describe how epigenetic processes have helped to shape the evolution of sex chromosome-linked genes. Furthermore, we compare features of escape genes on sex chromosomes in male germ cells to escape genes located on the single X chromosome silenced during X-inactivation in females, clarifying the distinct evolutionary implications between male and female escape genes.

    View details for DOI 10.4161/epi.25672

    View details for Web of Science ID 000327624600002

    View details for PubMedID 23880818

  • RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in post-meiotic spermatids GENES & DEVELOPMENT Sin, H., Barski, A., Zhang, F., Kartashov, A. V., Nussenzweig, A., Chen, J., Andreassen, P. R., Namekawa, S. H. 2012; 26 (24): 2737-2748

    Abstract

    Sex chromosomes are uniquely subject to chromosome-wide silencing during male meiosis, and silencing persists into post-meiotic spermatids. Against this background, a select set of sex chromosome-linked genes escapes silencing and is activated in post-meiotic spermatids. Here, we identify a novel mechanism that regulates escape gene activation in an environment of chromosome-wide silencing in murine germ cells. We show that RNF8-dependent ubiquitination of histone H2A during meiosis establishes active epigenetic modifications, including dimethylation of H3K4 on the sex chromosomes. RNF8-dependent active epigenetic memory, defined by dimethylation of H3K4, persists throughout meiotic division. Various active epigenetic modifications are subsequently established on the sex chromosomes in post-meiotic spermatids. These RNF8-dependent modifications include trimethylation of H3K4, histone lysine crotonylation (Kcr), and incorporation of the histone variant H2AFZ. RNF8-dependent epigenetic programming regulates escape gene activation from inactive sex chromosomes in post-meiotic spermatids. Kcr accumulates at transcriptional start sites of sex-linked genes activated in an RNF8-dependent manner, and a chromatin conformational change is associated with RNF8-dependent epigenetic programming. Furthermore, we demonstrate that this RNF8-dependent pathway is distinct from that which recognizes DNA double-strand breaks. Our results establish a novel connection between a DNA damage response factor (RNF8) and epigenetic programming, specifically in establishing active epigenetic modifications and gene activation.

    View details for DOI 10.1101/gad.202713.112

    View details for Web of Science ID 000312775700008

    View details for PubMedID 23249736

  • Human postmeiotic sex chromatin and its impact on sex chromosome evolution GENOME RESEARCH Sin, H., Ichijima, Y., Koh, E., Namiki, M., Namekawa, S. H. 2012; 22 (5): 827-836

    Abstract

    Sex chromosome inactivation is essential epigenetic programming in male germ cells. However, it remains largely unclear how epigenetic silencing of sex chromosomes impacts the evolution of the mammalian genome. Here we demonstrate that male sex chromosome inactivation is highly conserved between humans and mice and has an impact on the genetic evolution of human sex chromosomes. We show that, in humans, sex chromosome inactivation established during meiosis is maintained into spermatids with the silent compartment postmeiotic sex chromatin (PMSC). Human PMSC is illuminated with epigenetic modifications such as trimethylated lysine 9 of histone H3 and heterochromatin proteins CBX1 and CBX3, which implicate a conserved mechanism underlying the maintenance of sex chromosome inactivation in mammals. Furthermore, our analyses suggest that male sex chromosome inactivation has impacted multiple aspects of the evolutionary history of mammalian sex chromosomes: amplification of copy number, retrotranspositions, acquisition of de novo genes, and acquisition of different expression profiles. Most strikingly, profiles of escape genes from postmeiotic silencing diverge significantly between humans and mice. Escape genes exhibit higher rates of amino acid changes compared with non-escape genes, suggesting that they are beneficial for reproductive fitness and may allow mammals to cope with conserved postmeiotic silencing during the evolutionary past. Taken together, we propose that the epigenetic silencing mechanism impacts the genetic evolution of sex chromosomes and contributed to speciation and reproductive diversity in mammals.

    View details for DOI 10.1101/gr.135046.111

    View details for Web of Science ID 000303369600003

    View details for PubMedID 22375025

Footer Links:

Stanford Medicine Resources: