Dilworth Lab

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Contact Information

Jeff Dilworth, PhD
613-737-8899 ext. 70339

Research Activities

The goal of our research program is to understand the mechanisms by which tissue-specific patterns of gene expression are established during development, and how this can be reproduced in stem cells. While our interests cover all transcriptional regulatory factors, our current research focus is transcriptional activators implicated in myogenesis. This system has become the paradigm for studying gene expression during development due to the fact that exogenous expression of MyoD in a large number of cell lines is sufficient to initiate a temporally ordered and reproducible program of gene regulation leading to muscle differentiation. To understand how MyoD establishes muscle specific gene expression, our group is using a combination of biochemistry, cell biology, molecular biology, genomics, and proteomics.

We have played a leading role in the characterization of the importance for epigenetic enzymes in mediating the muscle regeneration process. Our group established that the Ash2L/MLL2 methyltransferase complex is targeted to muscle promoters by the ubiquitous transcription factor Mef2D through a mechanism requiring phosphorylation of Mef2D by p38 MAPK. We also showed that the histone demethylase UTX was targeted to muscle genes by the ubiquitous transcription factor Six4 to remove the repressive histone mark H3K27me3 thereby facilitating transcriptional elongation. Our finding that Six4 and Mef2D recruit TrxG proteins to specific muscle genes led us to propose a role of these ubiquitously expressed transcription factors in restricting gene expression to a specific subset of genes among the 25,000 target loci bound by MyoD in differentiating muscle. In addition, we discovered that the splicing of Mef2D to generate a muscle-specific isoform regulates its ability to be phosphorylated by PKA, a critical event that permits the transition from an HDAC-bound transcriptional repressor to an Ash2L/MLL2-bound transcriptional activator. More recently, we showed that the MyoD-interacting protein KAP1 plays a key role in enhancer assembly by acting as a platform for the recruitment of epigenetic enzymes to muscle specific promoters/enhancers. Thus, we have played a leading role in shaping our current understanding of the mechanism through which the ubiquitously expressed epigenetic enzymes are targeted to individual muscle genes in order to establish tissue-specific gene expression.

Our ongoing research is directed towards understanding the role of different transcriptional regulators in generating chromatin environments that establish and maintain tissue specific gene expression patterns.