The goal of this project is to elucidate the mechanism of epigenetic programming in germ cells, especially focusing on the roles of DNA damage response pathways in sex chromosome inactivation. Germ cells are capable of unique epigenetic programming which is required for sexual reproduction. A better understanding of the epigenetic program in germ cells will illuminate various reproductive issues underlying infertility and birth defects. When germ cells undergo male meiosis to generate haploid sperm, X and Y chromosomes go through a distinct epigenetic program different from autosomes. At the pachytene stage of meiosis, the genes on the X and Y are epigenetically silenced in a process called meiotic sex chromosome inactivation (MSCI). The entire X and Y chromosomes form a chromatin domain, known as the XY body, which is distinct from autosome regions. The XY body is marked by various chromosome-wide epigenetic modifications, which presumably maintain MSCI. My postdoctoral work revealed that sex chromosome inactivation is maintained even after meiosis, and implicated epigenetic inheritance in spermiogenesis and the embryonic development of the next generation. In this proposal, we aim to dissect the molecular basis of epigenetic silencing of sex chromosomes. An intriguing link between epigenetic silencing of sex chromosomes and components involved in DNA damage response (DDR) pathways has been suggested. Cytological evidence shows that various components involved in DDR pathways accumulate on the X and Y at the onset of MSCI. Based on our preliminary studies using mouse models defective for DDR pathways, we hypothesize that DDR pathways are adapted to initiate and maintain chromosome-wide silencing of sex chromosomes in germ cells. We will investigate the role of DDR pathways in MSCI by:
(Aim 1) determining how chromosome-wide silencing is initiated;
(Aim 2) dissecting the genetic pathways that coordinate potential downstream pathways;
and (Aim 3) determining how epigenetic modifications on sex chromosomes are established to maintain inactivation. The proposed study in germ cells will potentially reveal a link between DDR pathways and epigenetic programming that can be generalized to somatic cells.

Public Health Relevance

The mouse models in the proposed study exhibit male reproductive failure, indicating this research will identify mechanisms associated with male infertility. Because epigenetic defects in germ cells may affect embryonic development, the proposed study has significant relevance to the causes of birth defects. Also, identifying steps involved in the epigenetic silencing of sex chromosomes during male meiosis will lead to an understanding of the genetic cause of sex-linked aneuploidy, which results in Turner syndrome (XO) and Klinefelter's syndrome (XXY).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098605-04
Application #
8701301
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Carter, Anthony D
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Alavattam, Kris G; Kato, Yasuko; Sin, Ho-Su et al. (2016) Elucidation of the Fanconi Anemia Protein Network in Meiosis and Its Function in the Regulation of Histone Modifications. Cell Rep 17:1141-1157
Sin, Ho-Su; Kartashov, Andrey V; Hasegawa, Kazuteru et al. (2015) Poised chromatin and bivalent domains facilitate the mitosis-to-meiosis transition in the male germline. BMC Biol 13:53
Kato, Yasuko; Alavattam, Kris G; Sin, Ho-Su et al. (2015) FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis. Hum Mol Genet 24:5234-49
Broering, Tyler J; Wang, Yuan-Liang; Pandey, Ram Naresh et al. (2015) BAZ1B is dispensable for H2AX phosphorylation on Tyrosine 142 during spermatogenesis. Biol Open 4:873-84
Hu, Yueh-Chiang; Namekawa, Satoshi H (2015) Functional significance of the sex chromosomes during spermatogenesis. Reproduction 149:R265-77
Hasegawa, Kazuteru; Sin, Ho-Su; Maezawa, So et al. (2015) SCML2 establishes the male germline epigenome through regulation of histone H2A ubiquitination. Dev Cell 32:574-88
Du, Wei; Amarachintha, Surya; Erden, Ozlem et al. (2015) Fancb deficiency impairs hematopoietic stem cell function. Sci Rep 5:18127
Zhang, Tingting; Wilson, Andrew F; Mahmood Ali, Abdullah et al. (2015) Loss of Faap20 Causes Hematopoietic Stem and Progenitor Cell Depletion in Mice Under Genotoxic Stress. Stem Cells 33:2320-30
Broering, Tyler J; Alavattam, Kris G; Sadreyev, Ruslan I et al. (2014) BRCA1 establishes DNA damage signaling and pericentric heterochromatin of the X chromosome in male meiosis. J Cell Biol 205:663-75
Namekawa, Satoshi H (2014) Slide preparation method to preserve three-dimensional chromatin architecture of testicular germ cells. J Vis Exp :e50819

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