Epigenetics

Epigenetics in the limelight. Cover of the Epigenetics book, co-edited by Constellation’s founders

The approximately 40,000 genes identified by the Human Genome Project are now widely regarded as the code producing the building blocks that allow the human body to function. But in order to know where and when to act, the genes need instructions. This, in essence, is the role of epigenetics.

The DNA molecules in each cell, nearly 2 meters in length, are wound, like thread around a spool, on protein complexes containing histones. The DNA and the histones are collectively referred to as chromatin. Chromatin is unwound and opened to allow cells to use the genetic information in the DNA. It can also be compacted and closed to turn off its use, and allow DNA to be stored or transported. Changes in chromatin structure are controlled by the addition or removal of chemical modifications on chromatin, and these changes help control gene expression by silencing or activating genes at the correct times and in the correct locations. Improper gene activation or silencing by loss of epigenetic control can lead to aberrant gene expression that can drive the development of diseases such as cancer, autoimmunity, diabetes, or neurological disorders.

Supporting this theory, recent research has identified the set of enzymes and chromatin-binding proteins responsible for regulating chromatin structure.  There are several hundred enzymes that add and remove chemical modifications on chromatin – such as methyl marks and acetyl marks – and several hundred binding proteins that physically bind to chromatin through interaction with these chemical modifications.  These enzymes and binding proteins form the cell’s toolkit for epigenetic regulation by opening and closing chromatin or modifying chromatin structure to help control when and where genes are expressed.  Our research has shown that when epigenetic regulatory events occur aberrantly, the proteins that regulate these events can become drivers of disease.  Inhibiting these targets with novel agents promises to be a powerful avenue to develop important treatments serving unmet medical needs.