The Regulation of Chromatin Remodeling Complex SWR1C through Histone and DNA Interactions

ATP-dependent chromatin remodelers are gatekeepers of the epigenome, vital for regulating chromatin dynamics through controlling nucleosome spacing and structure. The tight regulation of remodeling mechanisms is essential to the normal development and function of an organism; dysfunctional or dysregulated chromatin remodeling is often associated with many human diseases and developmental disorders. Characterization of the structural and functional properties of remodeling mechanisms is becoming increasingly important to better understand and discover new interventions for various diseases. SWR1 is a multisubunit complex that catalyzes the exchange of the canonical histone H2A with its highly conserved variant H2A.Z, which is essential for genomic and cellular processes such as regulation of gene accessibility, transcription, translation, replication, and DNA break. However, the regulatory mechanisms governing the precise localization to correct sites, the specific interactions with the target substrates, and the adjustment of particular enzymatic machinery and mechanistic steps, are not yet discovered. Although extra-nucleosomal DNA and NuA4-mediated acetylation of the nucleosomes are identified to alter SWR1C-mediated dimer exchange, how these chromatin cues regulate SWR1 complex function is not clear. This thesis focusses on understanding the regulatory roles of nucleosomal elements, such as histone tails, acetylations, nucleosome-free linker DNA, and inter-nucleosomal interactions, on SWR1 complex function, as well as the corresponding function of the SWR1C ARP module.