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Apr 25, 2013
 |  BC Innovations  |  Cover Story

Super-enhancing discovery

Boston researchers have detailed a class of regulatory elements, dubbed super-enhancers, that control the expression of genes, including oncogenes, that are key to determining cellular identity.1,2 The findings may explain how some compounds that broadly inhibit particular epigenetic regulators can act selectively on oncogenes and could thus help identify new drug targets in cancer.

The team has founded Syros Pharmaceuticals Inc. to develop compounds that disrupt super-enhancers or the genes they regulate in cancer.3

Recent genomewide studies conducted as part of the Encyclopedia of DNA Elements (ENCODE) project have predicted hundreds of thousands to millions of enhancer elements in mammalian genomes that regulate gene expression.4 Complementing this effort, whole-genome maps of transcription factor binding sites in individual cell types have found that key regulators of cellular identity tend to work together to form large protein-DNA regulatory complexes at cell type-specific enhancers.

These regulators of cellular identity often control their own expression and that of their co-regulator proteins, forming positive feedback loops that help maintain a particular cellular phenotype.

The best-characterized example comes from embryonic stem cell (ESC) regulators including OCT4, SOX2 and nanog homeobox (NANOG). These sequence-specific DNA-binding factors occupy highly overlapping locations genomewide and control each other's expression and the expression of downstream genes that specify ESC identity.5

As expected, all three regulators are required to maintain ESC identity. What was unexpected was the recent demonstration that Mediator, a multisubunit protein complex that is a general coactivator of transcription in all cell types, also was important for determining ESC identity.6

Team leader Richard Young thus set out to understand how disrupting Mediator preferentially affects ESC-specific gene expression.

"Mediator is brought to nearly every active gene, yet when we reduce Mediator function in ESCs, it looks exactly like we reduced the levels of the key transcription factors," he said. "How is it that when you perturb a common regulator of gene expression, you can have a very specific kind of biological effect?"

Young is a member of the Whitehead Institute for Biomedical Research, professor of biology at the Massachusetts Institute of Technology and...

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