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Mammalian sex chromosomes are an excellent model system to understand the pivotal roles of epigenetic programming in development. Sex chromosomes precisely recapitulate stereotypical epigenetic programming in a timely and spatially-coordinated manner. In females, one of the X chromosomes is inactivated for dosage compensation of X-linked genes. In males, sex chromosomes are inactivated from meiosis to spermiogenesis in a process that is essential for germ cell developments. Meiotic sex chromosomes provide a unique opportunity which enable us to dissect the process of epigenetic programming. Following the initiation of meiotic sex chromosome inactivation, various epigenetic modifications are established gradually on the sex chromosomes in a coordinated manner. Such epigenetic modifications on the sex chromosomes are maintained through meiotic cell division into the spermatids, implying the inheritance of an epigenetic memory following meiosis. We investigate the underlying mechanism of sex chromosome inactivation specifically focusing the roles of DNA damage response pathways.
Figure 1 - Initiation mechanism of meiotic sex chromosome inactivation. (A) Schematic of sex chromosome inactivation. (B) MDC1 directs chromosome-wide spreading of gH2AX. Immunostaining of meiotic chromosome spreads using antibodies against gH2AX together with the anti-SCP3 antibody. SCP3 staining displays the status of chromosome synapsis and is used to distinguish meiotic stages. Areas surrounding sex chromosomes are highlighted in dotted rectangles and magnified in the right panels. (C) Pictorial representation about the role of MDC1 in MSCI. The first step is MDC1-independent recognition of the unsynapsed axis. The second step is MDC1-dependent spreading of gH2AX to the chromosome-wide domain. Ichijima et al Genes Dev 2011 25: 959-971
Sin HS, Kartashov AV, Hasegawa K, Barski A, Namekawa SH. Poised chromatin and bivalent domains facilitate the mitosis-to-meiosis transition in the male germline. BMC Biol. 2015 Jul 22;13:53.
Kato Y, Alavattam KG, Sin HS, Meetei A, Pang Q, Andreassen PR, Namekawa SH. FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis. Hum Mol Genet. 2015 Jun 29. [Epub ahead of print]
Hasegawa, K., Sin, H. S., 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., and Namekawa S.H. SCML2 establishes the male germline epigenome through regulation of histone H2A ubiquitination. Dev Cell. 2015 Mar 9;32(5):574-88.
Broering, T. J.*, Alavattam, K. G.*, Sadreyev, R. I., Ichijima, Y., Kato, Y., Hasegawa, K., Camerini-Otero, R. D., Lee, J. T., Andreassen, P. R., and Namekawa S. H. BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis. (*equal contribution) J Cell Biol, 2014 Jun 9;205(5):663-75.
Namekawa, S. H. Slide preparation method to preserve three-dimensional chromatin architecture of testicular germ cells. J Vis Exp. 2014 Jan 10;(83):e50819.
Hasegawa, K., Namekawa, S. H. and Saga, Y. MEK/ERK signaling directly and indirectly contributes to the cyclical self-renewal of spermatogonial stem cells. Stem Cells. 2013 Nov;31(11):2517-27. 2013.
Sin, H. S., and Namekawa, S. H. The great escape: active genes on inactive sex chromosomes and their evolutionary implications. Epigenetics. 2013 Sep;8(9):887-92.
Sin, H. S., Barski, A., Zhang, F., Kartashov, A. V., Nussenzweig, A., Chen, J., Andreassen, P. R., and Namekawa, S. H. RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in postmeiotic spermatids. Genes Dev. 2012 Dec 15:26(24)2737-2748.
Ichijima, Y., Sin,H. S., Namekawa, S. H.* Sex chromosome inactivation in germ cells: Emerging roles of DNA damage response pathways. Cell. Mol. Life. Sci. 2012 Aug;69(15):2559-72.
Payer, B.,* Lee, J. T., Namekawa, S. H.*X-inactivation and X-reactivation: Epigenetic hallmarks of mammalian reproduction and pluripotent stem cells. Hum Genet. 2011 Aug;130(2):265-80.
Ichijima, Y., Ichijima,M., Lou, Z., Nussenzweig, A.,Camerini-Otero,R. D., Chen,J., Andreassen,P. R., Namekawa, S. H.*MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes Dev.2011 May 1;25(9):959-71.
Namekawa, S. H.,* and Lee, J. T.* Detection of nascent RNA, single-copy DNA, and protein localization by immunoFISH in murine germ cells and pre-implantation embryos. Nature Protocols. 2011 Mar;6(3):270-84.
Namekawa, S. H., Payer, B., Huynh K. D., Jaenisch, R., and Lee, J. T. Two-step imprinted X-inactivation: Repeat vs genic silencing in the mice. Mol Cell Biol. 2010 Jul;30(13):3187-205.
Namekawa, S. H., Park, P. J., Zhang, L. F., Shima, J. E., McCarrey, J. R., Griswold, M. D., and Lee, J. T. Postmeiotic sex chromatin in the male germline of mice. Curr Biol. 2006 Apr 4;16(7):660-7.
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