James Bradner

Dana-Farber Cancer Institute
Department of Medicine
Harvard Medical School

Disruption of Super Enhancers

​Cell states are dynamically maintained by coordinated transcriptional programs. Master regulatory transcription factors localize to the genome in a manner influenced by chromatin accessibility and influencing global chromatin structure.  With an interest in understanding chromatin-dependent signal transduction to RNA polymerase in developmental and disease biology, we have undertaken to discover and optimize small-molecule modulators of chromatin regulatory factors that function at cis-regulatory elements (enhancers).  Specifically, we have undertaken to target epigenomic reader proteins that exhibit context-specific binding to acetylated chromatin at active enhancers driven by MYC transactivation in cancer.  This research has produced informative chemical probes, with which we have validated a hypothesis regarding the role of BRD4 in chromatin-dependent signal transduction from MYC to an elongating RNA polymerase.  To explain the MYC-specific transcriptional consequences of BRD4 inhibition, we have studied the genome-wide localization of BET bromodomains, finding high asymmetry in loading near to cell specifying transcription factors, locus control regions and previously unrecognized tumor dependencies.  Here, mechanistic insights into the role of super enhancers in cancer pathogenesis will be discussed, alongside data validating these structures as targets for further therapeutic exploration and immediate drug development.