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Genomic studies of mammalian gene regulation

  • Author(s): Huff, Jason Troy
  • Advisor(s): Yamamoto, Keith
  • et al.
Abstract

Much of biological complexity is achieved through regulated gene expression. In eukaryotes the rst step of gene expression involves transcription of DNA within chromatin to produce RNA, which often undergoes extensive processing co- and posttranscriptionally. Chromatin can aect one or more steps in gene expression at any number of genomic elements to achieve proper regulation. Furthermore, chromatin itself can be modied as a result of expression, thus bearing an epigenetic mark of gene activity that can be used for further regulation. Here, we used experimental and computational approaches in a variety of mammalian systems to establish how chromatin at various genomic elements is related to gene expression and co-transcriptional steps of RNA processing.

First, we used X chromosome-wide chromatin states to elucidate how genes can be expressed from within otherwise silent chromatin in humans. Second, we explored the mechanism of a chromatin-modifying complex in modulating mouse embryonic stem cell behavior. Last, we uncovered a correlation between chromatin structure and human gene architecture and gured out how this relates to RNA processing.

The results present a scenario in which transcribed genes contain active chromatin locally restricted to the genes proper, even in the midst of otherwise silent chromatin. The active chromatin in these regions is kept in such a state probably through the action of many factors. A corollary, specically that many factors can subsequently make use of chromatin marks, is also valid and in the case of embryonic stem cells, a chromatin complex makes use of an active mark at promoters to repress transcription for cellular self-renewal. Finally, we identied novel connections between active chromatin marks and introns and exons, which we propose are influenced through a mechanism involving co-transcriptional exon denition, a process previously thought to be important only in RNA processing. Analogously to active marks at promoters, these intronic and exonic chromatin marks could be subsequently used to regulate gene-centered DNA metabolism. In summary, these studies demonstrate the utility of genome-scale approaches in identifying features of gene expression in relationship to chromatin and produce several avenues for future research.

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