Strategies for Studying Chromatin Regulation and Organization

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Strategies for Studying Chromatin Regulation and Organization

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Title: Strategies for Studying Chromatin Regulation and Organization
Author: Nguyen, Son C. ORCID  0000-0003-2187-1027
Citation: Nguyen, Son C. 2016. Strategies for Studying Chromatin Regulation and Organization. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: The epigenetic regulation of gene transcription underlies the diversity between species and within organisms. Novel implementation of existing methods and the development of original technologies continue to contribute to the elucidation of chromatin complexity. Here, we present strategies to understand how chromatin is regulated and organized. First, we turned our attention to the Polycomb Group (PcG), which is composed of proteins that suppress transcription through the formation and function of complexes, including Polycomb Repressive Complex 1 (PRC1). Suppressor 2 of zeste (Su(z)2), a core subunit of the PRC1 complex, is composed of an N-terminal “homology region”, which contains domains involved in protein interactions, and the C-terminal region (CTR), which is believed to harbor the core activity of chromatin compaction. By conducting a mutagenesis screen and a classical genetics approach to dissect Su(z)2, we have made three key observations: the CTR is dispensable for viability, the core activity of Su(z)2 actually resides within the HR instead of the CTR, and an intramolecular regulatory cascade exists between the CTR and HR. These findings provide a novel framework on which to understand how different PRC1 activities may be regulated by Su(z)2. Secondly, since differences in chromatin regulation between cell types has been linked to differences in nuclear organization, we developed an adaptation of Oligopaints, a fluorescent in situ hybridization (FISH) technology, for the assessment of whole genome organization across single cells. We optimized the design of Oligopaint probe libraries and developed a new labeling strategy in order to improve cost-effectiveness and experimental flexibility for whole genome labeling. We also developed a new technology called OligoFISSEQ, which utilizes the whole genome libraries for the potential identification of all sub-megabase regions simultaneously. Together, these two strategies provide novel insights on how chromatin proteins and chromatin organization may be regulated.
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