Lindsey Ingerman James, Ph.D.

Our goal is to undertake innovative and novel projects focused on the chemical biology of chromatin regulation, with an emphasis on the development of small molecule antagonists and chemical probes for the domains that recognize the post-translational modification, methylated lysine. The modification of lysine residues by methylation has a central role in chromatin function, primarily through the creation of binding sites for proteins that recognize these marks. Aberrant methylation levels and ensuing changes in gene expression patterns resulting from the altered expression of methyl-lysine (Kme) regulatory proteins is one mechanism by which such epigenetic factors contribute to disease. Methyl-lysine readers have emerged as less precedented epigenetic targets, yet considering prior successes with acetyl-lysine reader antagonists and the abundant links between cancer genetics and Kme reader domains, they are well suited to become the next impactful target class of chromatin regulators for intervention via chemical probes.

We are interested in modulating the activity of chromatin reader proteins with small-molecule ligands, specifically potent and selective chemical probes, in order to open new avenues of research in the field of chromatin biology and potentially translate to compounds of therapeutic value. Our work in this area has pioneered the biochemical assays and medicinal chemistry strategies for high quality probe development for this untapped target class, as well as the means by which to evaluate probe selectivity, mechanism of action, and cellular activity. Using a variety of approaches, we utilize such chemical tools to improve our understanding of their molecular targets and the broader biological consequences of modulating these targets in cells. We are also developing novel methods and screening platforms to discover hit compounds to accelerate Kme reader probe discovery, such as affinity-based combinatorial strategies, as well as innovative techniques utilizing our developed antagonists to more fully understand the dynamic nature of chromatin regulation. Additionally, we have a specific interest in the application of antagonists for Kme reader domains, as well as other classes of epigenetic regulators, toward the study of HIV latency, as strategies that promote viral reactivation by disrupting repressive epigenetic processes represent a promising step toward a cure for HIV.