Year 5

Epigenetic processes include molecular pathways that modify the DNA or the proteins that are associated with DNA (i.e. histones), thereby affecting how the genetic information is read. Epigenetics plays an important role in normal biology and disease because it can affect how genes are turned on and off. Deregulation of epigenetic processes indeed contributes to disease development and progression including cancer. Our proposal has aimed to understand how the epigenome exerts its control over gene regulation. We have found that in addition to gene regulation, on epigenetic process is unexpectedly linked to control of cellular physiology. We have shown that dynamic acetylation of histone proteins regulates intracellular level of acidity, providing an unprecedented function for the epigenome. Our data provides plausible explanations for why ESCs contain in general higher levels of histone acetylation than other cell types and why certain cancers with low levels of histone acetylation are more aggressive. In a separate study, we have found that replication of DNA in ESCs is associated with a unique epigenetic signature that is not found in differentiated cells or other rapidly dividing cell types such as cancer. We have proposed that this molecular property of replication in ESCs may be an important determinant of continual cell division without malignancy, fundamentally distinguishing ESC-specific from cancer-like cell division. Altogether, we are providing novel insights into the functions of various epigenetic processes and how they may be similar or differ in stem cells vs. other normal and cancer cell types.