Mapping the Mouse Nucleosome Landscape through Chemical Biology

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Nucleosome organization influences gene activity by controlling DNA accessibility to transcription machinery. In this thesis, we have developed a chemical biology approach to determine mammalian nucleosome positions genome-wide. Using this strategy, we uncover surprising new features of nucleosome organization in mouse embryonic stem cells. In contrast to the prevailing model, we observe that for nearly all mouse genes a class of fragile nucleosomes occupies previously designated nucleosome-depleted regions around transcription start sites and transcription termination sites. We show that nucleosomes occupy DNA targets for a subset of DNA-binding proteins including CCCTC-binding factor (CTCF) and pluripotency factors Oct4, Sox2, Nanog, and Klf4. Furthermore, we provide in vivo evidence that promoter-proximal nucleosomes, with the +1 nucleosome in particular, contribute to the pausing of RNA Polymerase II. Lastly, we find a characteristic preference for nucleosomes to be positioned at exon-intron junctions. Taken together, we establish an accurate method for defining the nucleosome landscape, and provide a valuable resource for studying nucleosome-mediated gene regulation in mammalian cells.

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  • 01/29/2019
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