Molecular mechanisms of the core and linker histone tail domains that drive chromatin condensation

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Project Summary/Abstract: Human chromosomes serve to compact the genomic DNA several thousand times its length to fit within the cell’s nucleus, while also allowing for processes such as and gene expression. To accomplish this, the genome is assembled into a complicated, multifaceted complex known as chromatin. The assembly of chromatin first involves wrapping short (~200 bp) segments around spools of protein comprised of core histone into structures known as nucleosomes. Immensely long, genome-sized strings of nucleosomes are assembled into large structures via to the self-interacting nature of nucleosomes. The key elements in formation of these large condensed structures are the ‘tail’ domains of the core histone proteins, which protrude out from the main body of nucleosomes to mediate inter-nucleosome interactions. However, despite their essential nature to the formation of chromosomes, little is actually known about how the histone tail domains contact neighboring nucleosomes. Moreover, these interactions represent critical points for regulation, and are modified by epigenetic posttranslational modifications, including acetylation, as well as other chromatin modifiers. This project will employ biochemical and biophysical techniques to define critical molecular aspects of the inter-nucleosome interactions mediated by the core histone tail domains in model systems, and elucidate how epigenetic modifications within the tail domains regulate these interactions. The specific goals of the work described in this proposal are to: 1) define inter- nucleosome interactions mediated by the core histone tail domains, and how posttranslational modifications transition inactive chromatin structures to those hospitable to active genes in a model chromatin system; 2) define aspects of how linker histones bind to nucleosomes, and oligonucleosome arrays, are affected by posttranslational modifications, and communicate the core histone tail domains; and 3) understand how the HMGN chromatin architectural factors influence H1 structure to destabilize chromatin condensates In addition, we will use lessons learned from the above work to understand the molecular basis a newly identified mutation in a linker histone that causes the genetic disorder known as Rahman’s disease. These results will fill in key knowledge gaps in our understanding of how chromosomes are assembled, and regulated to provide for transcription, replication, DNA repair, and other genome-related processes.