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Regulation of gene accessibility from nucleosome occlusion to heterochromatin architecture

Abstract

The assembly of eukaryotic chromatin is critical for gene regulation and nuclear packaging. DNA is wrapped around histone proteins to form nucleosomes, and these structures are inherently repressive, blocking the binding of most DNA factors. Chromatin generally exists in two domains, active euchromatin and silenced heterochromatin, and chromatin modifications serve as signals to regulate these regions. In this thesis, we investigate the mechanisms by which two heterochromatin proteins, Swi6 and Chp2, function to regulate gene silencing. While these are similar proteins, they have separate, non-overlapping functions. We hypothesize that many of their biochemical and biophysical properties can explain their differing behaviors in vivo. In this thesis, we show how these proteins differentially recognize regions of binding partners that help form and regulate chromatin domains. We show that these proteins oligomerize to similar extents, but have varied affinities for nucleosomal structures. In addition, we show that Chp2 and Swi6 conformations are differentially regulated. In addition to these silencing proteins, we examine how CRISPR-Cas9, a protein used for genome editing that originated in bacteria, is affected by euchromatin structures. We show that dynamic nucleosomal structures are permissive to the activity of Cas9, and this protein can take advantage of other chromatin modifying enzymes to access the underlying DNA. This work will contribute to the understanding of how different proteins interact with chromatin structures, modify it, and change chromatin packaging and structures.

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