"The importance of super-enhancers in transcriptional regulation during development and disease"

The importance of super-enhancers in transcriptional regulation during development and disease”

Dr. Warren Whyte
Whitehead Medical Institute
Wed, 2/20/2013 - 4:00pm

221 Integrated Science Building

Transcription factors bind enhancer elements and recruit chromatin regulators to activate genes in cells. We report here that certain key transcription factors and the chromatin regulator Mediator form “super-enhancers” at key cell identity genes in mammalian cells. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of transcription factors and chromatin regulators. Reduced levels of these regulatory proteins cause preferential loss of expression of super-enhancer -associated genes relative to other genes, implicating super-enhancers in the control of mammalian cell identity and development.

In cancer, chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. We also report that inhibition of the widely-expressed chromatin regulator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co- occupy a small set of super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of tumor cells with the Brd4 inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including the MYC oncogene. Super- enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types.


Refreshments at 3:45pm