Biology

Srimonta Gayen, PhD
University of Michigan Medical School

Emerging evidence implicates that epigenetics plays a major role in developmental processes. However, often dysregulation of epigenetic processes leads to different human diseases such as cancer. Unlike irreversible mutations in DNA, epigenetic modifications are reversible. This inherent plasticity makes epigenetic changes associated with human diseases potentially amenable to manipulation via therapeutic intervention. Therefore, understanding of epigenetic regulation is crucial for our comprehension of the alterations that can lead to disease. However, much about the mechanistic aspects of epigenetic regulation remains to be understood. In recent years, long non-coding RNAs (lncRNAs) and histone modifiers have emerged as the key players in epigenetic regulation. My research strives to elucidate the mechanism of epigenetic regulation with a focus on lncRNAs and histone modifiers through the study of X-chromosome inactivation using mouse embryos and stem cells. X-inactivation is a process by which female mammals compensate the dosage of X-linked gene expression between XY male and XX female, via transcriptional silencing one of the two X-chromosomes. X-inactivation is a paradigm of lncRNA and chromatin control biology. X-inactivation is thought to be controlled in cis by a pair of oppositely transcribed X-linked lncRNAs, Xist and Tsix. However, I discovered that the Tsix lncRNA is dispensable for the initiation of X-inactivation and ectopic expression of Xist lncRNA, in male cells, is insufficient to inactivate the sole X-chromosome. I therefore next addressed a central question in biology – what causes female but not male cells to undergo X-inactivation. I found that the higher dose of the SMCX (Histone demethylase) protein in females causes the female-specific induction of X-inactivation.

My future research will be focused on (1) elucidation of the mechanism of epigenetic reprogramming of cell fate, including X-chromosome reactivation and (2) elucidation of the role of epigenetic dysregulation in cancer. My ultimate vision is that site-specific epigenetic editing, will be a better approach in cell fate reprogramming and epigenetic therapy of cancer. I will test and implement this strategy using the CRISPR/Cas9 system. The long-term goal of these studies is not only to advance our understanding of basic epigenetic mechanisms in gene regulation, but also to provide critical insights into developing new therapeutic approaches to treat human disease such as cancer.