The sex chromosomes of mammalian germ cells must match those of the surrounding soma in order for the germ cells to successfully complete development as sperm or eggs. Surprisingly, however, the sex chromosome-encoded factors acting in the germ cells to ensure compatibility with the soma remain unknown. This proposal will test the hypothesis that two pairs of homologous demethylase genes encoded by the X and Y chromosomes coordinate male- and female-specific chromatin states in the developing germ cells, enabling them to respond appropriately to sex-specific signals from the surrounding soma. These two pairs of X-Y histone demethylase homologs target H3K4me3 and H3K27me3, two chromatin marks that play a central role in regulating the balance between pluripotency and differentiation. By setting up different chromatin states at important promoters in XX and XY germ cells, the X/Y-encoded demethylases may predispose these cells to respond differently to cues from XX or XY somatic tissue, thus enabling appropriate male or female gamete differentiation. This hypothesis has two implications: that the chromatin state of male and female germ cells differs even before their appearance and behavior diverges, and that the histone demethylases encoded on the X and Y chromosomes are at least partly responsible for this difference in chromatin state. This proposal will address each of these implications separately, by (1) determining whether histone methylation states differ between males and females just before their developmental programs diverge, and (2) evaluating the role of the X- and Y-chromosome-encoded demethylase genes in setting up sex-specific chromatin states. Fulfillment of each of these aims will enhance our current understanding of sex-specific gamete development, and improve clinical approaches to disorders of fertility and early embryonic development.

Public Health Relevance

All the genetic information required to produce a healthy embryo and a healthy child is carried from parent to offspring through sperm and eggs, also called the germ cells. Any problems during the progression from precursor cell to sperm or egg can result in infertility or impaired child development, but the signals governing this progression are still incompletely understood. This proposal will investigate the role of specific genes on the X and Y chromosomes in controlling genome packaging in developing sperm and eggs, and determine whether defects in the function of these genes are responsible for some cases of infertility and developmental disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Taymans, Susan
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Whitehead Institute for Biomedical Research
United States
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Alpatov, Roman; Lesch, Bluma J; Nakamoto-Kinoshita, Mika et al. (2014) A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell 157:869-81
Lesch, Bluma J; Page, David C (2014) Poised chromatin in the mammalian germ line. Development 141:3619-26
Lesch, Bluma J; Dokshin, Gregoriy A; Young, Richard A et al. (2013) A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis. Proc Natl Acad Sci U S A 110:16061-6