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Exploring the function of histone modifying enzymes during development
A large number of enzymes that post-translationally modify histones/DNA have been identified and biochemically characterized. A number of these enzymes have also been shown to be essential for embryo development, mutated in cancers and neurological disease, or important for transgenerational epigenetic inheritance in model organisms. We are using stem cell based models of development along with mouse genetics to remove enzymes that post translationally modify histones and DNA in a tissue specific manner. In particular we are focusing on the time period of preimplantation development, where massive reprogramming of the epigenome takes place, and during formation of the central nervous system, when cells are becoming post-mitotic as they differentiate into neurons and are thus incapable of replication dependent changes in the epigenome. With these studies, we hope to gain a further understanding of the importance of epigenetic information stored in chromatin.
Studying the interplay of transcription factors and chromatin modifying enzymes
Transcription factors have long been known to be the master regulators of cell fate, binding to specific sequences of DNA and activating or silencing genes that allow specific cell types to carry out specialized function. More recently, it has been demonstrated that transcription factors can convert somatic cells into induced pluripotent cells (iPS cells) or from one somatic type to another, although this process is relatively inefficient. One likely reason this process is so inefficient is that differentiated cell types carry "restrictive" epigenomes that are less accessible to transcription factors than the "permissive" epigenomes of embryonic stem cells, which are easily reprogrammed to somatic cells. We are thus exploring the possibility that chromatin-modifying enzymes gate the activity of transcription factors during these reprogramming processes (both natural and artificial reprogramming), and are testing how chromatin-modifying enzymes work in conjuction with transcription factors to regulate cell fate.
Exploring the regulation and function of endogenous retroviruses
Endogenous retroviruses (ERVs) are the remnants of ancient retroviral infections that have become a permanent part of the host genome. These sequences make up nearly 10% of mammalian genomes. It has long been debated whether ERVs and other transposable elements are nothing more than parasitic elements that have remained in genomes due to their ability to independently replicate (via retrotransposition) or whether they may provide some selective advantage to their hosts. One way in which ERVs can influence their hosts is via regulation of host gene expression. ERVs and other transposons are targeted for silencing by distinct repressive chromatin generating machinery that can spread to neighboring genes, or can serve as alternate promoters. We have been studying a particular class of ERVs found in all placental mammals called ERVLs (MERVLs in the mouse) that very briefly evade silencing in preimplantation development during zygote genome activation. Morever these ERVL elements appear to serve as primary or alternate promoters for a large number cellular genes, which has lead us to speculate that these elements may actually be essential for embryo development. We are interested in two important questions, 1) How are ERVL elements regulated? and 2) Are ERVL elements critical for cell fate decisions in embryo development?