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.
