Mechanistic Investigation and Engineering of Histone Reader Proteins

Abstract. The integral roles of histone post-translational modifications (PTMs), including lysine methylation and acylation, in chromatin remodeling is well established, but new roles of histone PTMs in disease are continually discovered. This rapidly evolving field necessitates the development of new molecular approaches to probe the biological impacts of these PTMs. Herein we focus on the reader proteins for lysine methylation and acylation as reader proteins are responsible for sensing the PTM and triggering the biological outcome, and both r have biomedical relevance. Our research will encompass development of new chemical biology tools to investigate binding mechanisms, improve detection of PTMs, and to generate designer nucleosomes to study the role of dual PTMs in biological pathways. This research is expected to advance the ability to develop selective inhibitors and molecular probes for these two classes of proteins. To develop new methods for creating new sensing methods and designer nucleosomes, we will exploit the inherent selectivity of reader proteins to develop engineered reader proteins (eReaders and eWriters) for sensing, labeling, and introduction of dual PTMs in a site selective manner. This combined effort will advance the field by providing new insight and new tools to study the biological pathways that depend on these PTMs and their role in disease.