2:27 PM
Oct 26, 2017
 |  BC Innovations  |  Tools & Techniques

Ripe for enhancement

How advances in enhancer profiling can aid drug development

Although still largely the purview of academics, technologies for mapping enhancers to the genes they control are rapidly gaining efficiency and promise to unlock a trove of new targets for drug developers. But companies will need to contend with complex biology and screens that require primary human cells.

The progress adds another branch to the field of epigenetics, an area seeing revived interest in translational science as researchers find solutions in human data that answer mechanistic questions and guide drug discovery around HDACs, BET bromodomain proteins and emerging epigenetic targets.

An advantage of enhancers is that they offer an avenue for tissue-specific manipulation of gene expression, a major goal of industry.

Enhancers are regulatory regions in the genome that control the levels, timing and spatial pattern of gene expression. They are more numerous and diverse than promoters - whose job is to kick off the process of transcription - and provide a higher level of regulation, mediating state- and cell type-specific expression patterns.

Individual genes are often controlled by multiple enhancers that are active in different cell types and under different conditions, which has complicated the task of unraveling the biology.

But academic studies over the last five years suggest that understanding where and how enhancers operate could produce a step change in deciphering how SNPs in non-coding regions influence susceptibility to disease.

“The basic issue is that the non-coding sequence is greater than 95% of the genome, and most trait-associated variation falls into non-coding sequences, especially in enhancers and promoters,” Massachusetts Institute of Technology (MIT) Professor Richard Young told BioCentury.

Young is co-founder of Syros Pharmaceuticals Inc. and Marauder Therapeutics Inc., the only two companies to date based on an enhancer platform, according to BioCentury’s Archives.

“The dark matter has more functionality, which has been known for a long time. The challenge has been to sift through the intergenomic regions to find what is relevant.”

Jay Bradner, NIBR

James (Jay) Bradner, who co-founded Syros together with Young and Dana-Farber Cancer Institute professor Nathanael Gray, told BioCentury the problem has been in separating the wheat from the chaff. Bradner is now president of the Novartis Institutes for BioMedical Research (NIBR).

“The dark matter has more functionality, which has been known for a long time. The challenge has been to sift through the intergenomic regions to find what is relevant,” Bradner said.

According to John Stamatoyannopoulos, professor of genome sciences and medicine at University of Washington, the difficulty is partly because enhancers can be located either upstream or downstream of a transcriptional start site and can be hundreds of kilobases away, with several, unrelated genes falling in between.

“The chief obstacle to progress is the difficulty to connect a disease variant to the actual target gene. It’s one thing to say a variant localizes in an enhancer and a different thing to say that enhancer controls this gene over here,” said Stamatoyannopoulos.

He added that enhancer screens require careful set up and may not yield relevant results if carried out in standard laboratory cell lines. “Enhancers are cell type- and state-specific; if you use cancer cell lines, well,...

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