The overall goal of our research is to investigate epigenetic mechanisms underlying disease states.
The basic questions that interest us are (a) how do epigenetic mechanisms regulate gene expression (b) what is the order of these changes, and (c) can we reverse these processes to better manage disease?
What is Epigenetics?
Epigenetics, meaning "above the gene", is defined classically as changes in gene expression that are stably inherited, but are not caused due to alterations of the DNA sequence itself. In eukaryotes, the highly complex structure known as chromatin (DNA, histones and other proteins) plays an important role in gene expression. The prevailing model for gene regulation is targeted recruitment: activators and repressors bind to specific DNA sequences, and recruit chromatin-modifying protein complexes that modify chromatin, thus allowing or restricting access to the genetic information.
Epigenetic changes are heritable and include histone modifications, alterations in chromatin structure, small non-coding RNAs and DNA methylation, and are generally associated with altered gene expression. Often, they occur in combination: for example, epigenetic marks such as the trimethylation of the histone H3 lysine 9 residue (H3K9me3) and DNA methylation are associated with repressed and/or silenced genes in many model systems. Epigenetic modifications of our genome affect transcription regulation and are involved in a broad range of human diseases, including cancer metastasis.
Epithelial to Mesenchymal Transition (EMT)
Metastasis is a critical event in cancer progression that involves the spread of tumor cells from a primary cancer to secondary sites in the body, thus rendering the effective management of cancer extremely difficult. The misregulation of several normal biological pathways contributes to metastasis.
In particular, a process known as 'Epithelial to Mesenchymal Transition' (EMT), which causes cells to change their shape and migrate during development, is hypothesized to play an important role in metastasis. Our research aims to understand the epigenetic and molecular basis of EMT. Specifically, our lab is interested in two highly related transcription factors, Snail and Slug, which regulate the expression of genes that are essential for EMT.
The Snail and Slug transcription factors in EMT
Snail and Slug are primarily repressors of transcription that recognize and bind to the same minimal DNA sequence, CAGGTG, and elicit changes in the epigenetic landscape of genes by recruitment of co-factors such as the histone lysine demethylase LSD1, the polycomb repressive complex PRC2, and Histone deacetylases (HDACs). This causes cells to become migratory, invasive, and de-differentiated, leading to metastasis. In the image below, loss of E-cadherin (red), a cell-cell adhesion protein, following induction of EMT is seen.
Using breast cancer cells as our model system, we propose to investigate the mechanisms utilized by Snail and Slug to bring about gene repression leading to EMT. As our understanding of epigenetic mechanisms of EMT increases, the challenge will be to develop new drugs to specifically target and reverse each epigenetic lesion.
The rationale for our proposed research is that detailed elucidation of the epigenetic mechanisms in EMT will provide valuable insights into the pathology of cancer metastasis, provide the basis for translational cancer research, and in the long term, will identify new targets for the personalized management of cancer metastasis.
Volunteer your computer for research: DNA@home
DNA@Home is a joint effort between Dr. Travis Desell in the Computer Science Department and the Basic Sciences Department of the University of North Dakota and has been developed with support from Rensselaer Polytechnic Institute. We are currently using DNA@home to search for transcription factor binding sites that might influence Snail and Slug dependent gene regulation. DNA@home uses statistical algorithms to identify binding sites using your volunteered computers.