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Epigenetic Regulation of Transcription and Cellular Potency during Mammalian Development

  • Author(s): Sachs, Michael
  • Advisor(s): Ramalho-Santos, Miguel
  • et al.
Abstract

DNA provides the blueprint for all cellular functions through the process of gene transcription, while epigenetics contributes to regulating which genes are transcribed and to what extent. Both this genetic and epigenetic information must be passed from one cell to its daughters to preserve cellular identity. The accessibility of DNA to the transcriptional machinery is regulated by a multitude of chromatin proteins and complexes. Chd1 is a highly conserved enzyme chromatin remodeler essential to mammalian development. Despite its strong association with transcriptional activity, its precise role remains unclear. In chapter 2 of this dissertation I present evidence showing that Chd1 is dispensable for in vitro pluripotency, but is required for optimal expansion of mouse ES cells, a defect that likely results from a wide-spread reduction of RNA polymerase activity, which is known to limit cell cycle progression. This is a novel chromatin level regulation of cell proliferation.

In addition to regulating transcriptional initiation and elongation, chromatin packages DNA into domains that are either available for transcriptional activation or not. Bivalent domains are a unique chromatin state associated with pluripotency that maintain gene promoters as poised, in an available but inactive state, for rapid activation upon lineage specification. In chapter 3, I describe the observation of bivalent domains in the unipotent mammalian germline during embryogenesis. These domains are enriched for developmental regulators of all germ layers in a manner remarkably similar to ES cells. The maintenance of the somatic program in a poised state in the germline throughout development raises the intriguing possibility this epigenetic information imparts a path for transgenerational epigenetic inheritance.

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