The goal of this proposal is to delineate the molecular mechanisms by which the BET class of bromodomain proteins control gene regulation.
Many diseases involve the deregulation of gene expression. Recently, a new field has emerged in which gene regulatory proteins have been successfully
pursued as therapeutic targets. However, our grasp of the biochemistry of these targets has lagged behind the pursuit of inhibitors.
Bromodomain proteins, and in particular the BET family of bromodomain proteins, is one such class of proteins. Despite enormous promise shown in the
inhibition of these proteins for the treatment of a range of diseases, a clear understanding of their biochemical functions is lacking and the current generation
of inhibitors shows no selectivity for family members. We will address the biochemical functions of these proteins. The results of this work will both broaden
our understanding of gene regulation and support the search for more selective epigenetic therapeutics.
Our hypotheses are that: (i) interactions made by the ET domains of BET proteins with chromatin remodeling complexes plays a role in BET protein activity;
(ii) the coiled-coil domains in BET proteins regulate their function through homo- and heterodimerization; and (iii) BRD2/3 interact directly with CTCF and
acetylated H2A.Z to regulate chromatin boundary formation.
We have established the following aims:
Aim 1. Establish how the interaction of the ET domain with chromatin remodellers impacts BET-protein function.
Aim 2. Determine the roles of the putative coiled-coil domains in BET-family proteins.
Aim 3. Define the molecular mechanism by which BRD2/3 enforce chromosomal boundaries.