Abstract

Chemogenomic Approaches to Spatiotemporal Regulation of HDAC Activity

Ralph Mazitschek, Assistant Professor, Broad Institute Of MIT And Harvard

Epigenetic mechanisms are critical to the regulation of activity-dependent gene expression and play key roles in many physiological processes including cell proliferation, neuroplasticity, and regulation of the circadian clock. These dynamic processes are orchestrated by chromatin-modifying enzymes including histone deacetylases (HDACs), which have been recognized as master regulators of chromatin structure and function. Beyond modulating histone acetylation they are recognized as regulators of non-histone proteins. The utilization of small-molecule probes as tools to interrogate the biology of epigenetic gene regulation has tremendously increased our knowledge and provided detailed insights into mechanisms essential to the dynamic regulation of the human genome. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatio-temporal control. To address these shortcomings we have developed a new approach, referred to as ‘Chemo-Optical Modulation of Epigenetically-regulated Transcription’ (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light.