Andrew J. Andrews, PhD
Office Phone: 215-728-5321
Lab Phone: 215-728-3558
DNA is highly compacted to fit into cells. The initial compaction forms the nucleosome, with each nucleosome consisting of two copies of four histone proteins H2A, H2B, H3 and H4. A major mechanism regulating the accessibility of DNA for the purposes of transcription, replication, DNA recombination, and DNA repair is through post-translational modification (PTM, or chemical modification) of histones. The most common PTMs are acetylation and methylation, with multiple residues targeted on each of the histones. Specific PTMs and their location are associated with either activated or repressed states of chromatin.
Changes in histone acetylation correlate with changes in disease. The importance of maintaining proper histone post-translational modifications is made clear by the numerous diseases that correlate with misregulation of these modifications: cancer, heart disease, fetal alcohol syndrome, and Alzheimer’s, to name a few. Specifically, these diseases have each been shown to lack adequate levels of histone acetylation at specific locations. In order to maintain the proper level of acetylation in a healthy cell, lysine acetyltransferases (KATs) are responsible for targeting specific lysines in the histone. Despite the importance of this biological activity, relatively little is known about the factors that influence the location and extent of these post-translational modifications. Understanding how histone acetylation is regulated and, importantly, how it can be manipulated by the environment or through the use of pharmacological agents would allow us to tailor treatments to reverse or even prevent those diseases associated with loss of specific histone acetylation.