6:20 PM
Jan 17, 2019
 |  BC Innovations  |  Targets & Mechanisms

Exploring 3-D genomic white space

How 3-D chromatin structures open up a higher level of gene regulation control

Gene regulation is offering a new class of targets that operate on a higher level than DNA sequences and epigenetic markers: 3-D genomic structures. While strategies to drug the 3-D genome are still in their infancy, the growing accessibility of mapping technologies is paving the way for translation in cancer and developmental disorders.

DNA has long been known to wrap around histone protein complexes in stretches of about 150 bases, forming chromatin that is made more or less accessible by epigenetic modifications, such as lysine and methyl tags. However, less is understood about the higher order chromatin loops and clusters, known as topologically associating domains (TADs), which involve DNA stretches on the order of tens of kilobases to several megabases.

In the last five years, advances in sequencing- and imaging-based methods to characterize these structures have catalyzed research studies dissecting their role in controlling gene expression.

The question is whether better understanding of the 3-D genome will yield therapies that correct dysfunctional gene expression in disease.

“The factors that govern chromatin topology are likely to represent powerful targets for drug discovery.”

Cigall Kadoch, Dana-Farber Cancer Institute

3-D genome targeting is farther away from translation than targeting enhancer and promoters or developing epigenetic modulators. But the payoff, compared with those approaches, could be greater potency, particularly in diseases such as cancer or fragile X syndrome, where gene expression is dysregulated on a large scale.

“The factors that govern chromatin topology are likely to represent powerful targets for drug discovery,” said Cigall Kadoch, co-founder of Foghorn Therapeutics Inc.“We now know from a wide range of studies by our lab and others that perturbation to chromatin regulating machines, particularly remodeling complexes, can massively affect global DNA accessibility.”

Kadoch is assistant professor of pediatric oncology at Dana-Farber Cancer Institute, and an institute member and Epigenomics Program co-director at the Broad Institute of Harvard and MIT.

Foghorn, which launched last year with a $50 million series A round from Flagship Pioneering, is developing small molecules that disrupt the pathogenic activity of mutated chromatin remodeling complexes, to restore normal 3-D genomic structure and function. Former Bristol-Myers Squibb Co. SVP and head of discovery...

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