Research Departments & Organizations
Cellular Reprogramming; Chromatin Assembly and Disassembly; DNA Packaging; Embryonic and Fetal Development; Evolution, Molecular; Fertility; Gene Expression Regulation; Germ Cells; Heredity; Infertility; Mice; Paternal Age; Reproduction
Germ cells (sperm, eggs, and their developmental precursors) carry the genome from one generation to the next. The germ cell nucleus therefore carries all the information that will guide the development of the next generation, and that will subsequently be passed to future generations to ensure the survival of the species. How the physical genome is handled within the germ cells thus has significant implications for development of individuals and for evolution of species. Our lab aims to define how packaging of the genome in germ cells influences these processes. We compare chromatin states in germ cells across species to understand how genome regulation has evolved, and we use mouse genetics to model the molecular basis of these processes and their direct effects on embryo development.
We have previously shown that epigenetic poising, a chromatin state characterized by the simultaneous presence of both activating and repressive histone marks and strongly associated with pluripotent stem cells, is a fundamental characteristic of mammalian germ cells beginning at early stages of development and specifically marks genes required for embryogenesis in the next generation. Furthermore, poising is conserved in the amniote germ line, but evolves at specific locations in individual lineages in conjunction with developmental innovations. These findings imply that poising in the germ line may help to protect or ‘set aside’ regions of the genome that are particularly important for early embryonic development. We are currently pursuing this hypothesis, as well as examining additional aspects of germ cell genome regulation. See the lab website for more information about current projects.
Parallel evolution of male germline epigenetic poising and somatic development in animals.
Lesch BJ, Silber SJ, McCarrey JR, Page DC. Parallel evolution of male germline epigenetic poising and somatic development in animals. Nature Genetics 2016, 48:888-94. 2016
Poised chromatin in the mammalian germ line.
Lesch BJ, Page DC. Poised chromatin in the mammalian germ line. Development (Cambridge, England) 2014, 141:3619-26. 2014
A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.
Alpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, Stützer A, Armache KJ, Simon MD, Xu C, Ali M, Murn J, Prisic S, Kutateladze TG, Vakoc CR, Min J, Kingston RE, Fischle W, Warren ST, Page DC, Shi Y. A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell 2014, 157:869-81. 2014
A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis.
Lesch BJ, Dokshin GA, Young RA, McCarrey JR, Page DC. A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110:16061-6. 2013
The ligand binding domain of GCNF is not required for repression of pluripotency genes in mouse fetal ovarian germ cells.
Okumura LM, Lesch BJ, Page DC. The ligand binding domain of GCNF is not required for repression of pluripotency genes in mouse fetal ovarian germ cells. PloS One 2013, 8:e66062. 2013
Genetics of germ cell development.
Lesch BJ, Page DC. Genetics of germ cell development. Nature Reviews. Genetics 2012, 13:781-94. 2012