We are broadly interested in the intersection of evolution, developmental biology, and gene regulation. We use a combination of molecular biology, bioinformatics, and model organism genetics to address the following:
Comparative evolution of germline chromatin state
Germ cells are necessary for fitness: an organism without functional germ cells cannot reproduce, and has an adaptive fitness of zero. Germ cells are therefore direct targets of natural selection. In particular, differences in sperm morphology and function can mediate competition for reproductive success between males, and sperm-specific proteins often exhibit evidence of rapid sequence evolution. We are exploring how these strong selective pressures impact genome packaging and gene regulation in developing sperm, and how selection on germ cells can in turn affect the regulatory biology of the genome more generally.
Biological role of epigenetic poising in the germ line
We are especially interested in a specific regulatory state, called epigenetic 'poising' or bivalency. Poising is defined by the simultaneous presence of two histone modifications: H3K4me3, usually associated with transcriptional activation, and H3K27me3, usually associated with transcriptional repression. The presence of significant numbers of poised loci in the nucleus is associated with broad developmental potential (pluripotency). Genes marked by the poised state are transcriptionally repressed, but the presence of the activating modification H3K4me3 is thought to 'poise' them for activation as the pluripotent cell differentiates. We and others have shown that mammalian germ cells maintain a poised state at promoters of genes required for somatic tissue development, even though they are terminally differentiated as sperm or eggs. This intriguing contradiction implies that poising in germ cells may play a role in the germ cells' ability to re-establish totipotency, the ability to make any cell in the body, in the embryo at fertilization.
We have defined two types of poised genes in mammalian male germ cells: those at which poising has been conserved since before the time of the mammalian common ancestor, and those where it is more rapidly evolving. Starting from this point, we are working to further characterize the evolutionary dynamics of the poised state in the germline. Specifically, we would like to answer the following questions: When did poising first arise in the animal lineage? Can newly-evolved sequences gain poising, and if so, what characteristics predispose them to do so? What selection pressures drive divergence of poising between species?
We are also searching for regulators of poising using a variety of approaches, including evaluation of existing mouse mutants and Cas9-based screening for new candidates, using both cell culture and in vivo mouse model systems.
Effects of germline regulatory information on the next generation
Male germ cells transmit the paternal genome to the next generation. At the same time, they also transmit packaging proteins that carry regulatory information. As a natural extension of our studies of germline regulatory state, we are investigating how transmission of these regulatory states through sperm may affect somatic development in the next generation. Specifically, we are testing the hypothesis that epigenetic poising in germ cells contributes to the activation of these somatic developmental regulators after fertilization. We have also defined a transgenerational effect on disease susceptibility following germline knockout of a specific histone modifying enzyme, and are working to further characterize this effect.