Faculty Summaries
Dr. Andrews
Andrew J. Andrews, PhD
Assistant Professor
Office Phone: 215-728-2762
Lab Phone: 215-728-2762
Office: P3133
Lab: P3117
  • 1. Protein-protein networks that govern the residue specificity of histone actylation.

    Acetylation is a potentially powerful drug target but development has been hindered by the complexity of the protein-protein networks that govern acetylation. Detailed thermodynamic data on the interactions of histone chaperones and histone modification enzymes, and an experimental/mathematical way in which to tackle more complex systems is central to understanding many human diseases (p300). By understanding these processes, we will also be able to determine which complexes and conditions (acetyl-CoA concentrations) support residue specific acetylation verses more global histone acetylation. In turn, this information will allow us to assemble and target the key complex needed to favor residue specific acetylation.

    Possibly the most innovative feature of this project is the ability to measure and predict the location and amount of acetylation at a specific residue on a specific histone, as well as to determine its effect(s) on chromatin dynamics. This may solve the mystery of why CBP/p300 is both a tumor suppressor and promotor. We know that KATs acetylation targets can be altered by binding partners it is likely that these altered locations of modification have different impacts on chromatin either by altering the thermodynamics or other chromatin binding proteins. Having both ends of this data (what is acetylated and what is the impact of acetylation) will allow us to make predictions about what to expect in vivo. This would lead to a new bottom up approach to biomarker identification.

  • 2. The impact of post-translational modifications on the thermodynamics of chromatin

    It has often been stated, although never proven directly, that PTMs alter the thermodynamics of the nucleosome or nucleosome-nucleosome interactions, thereby regulating access to DNA. I have devised a method for measuring the thermodynamic constants that govern nucleosome formation. This exciting breakthrough allows us for the first time to measure the effects of acetylation and other modifications on nucleosome thermodynamics. This approach also provides unprecedented insight into how histone acetylation affects histone homeostasis, with histones redistributing between histone chaperones and nucleosome if the affinity of histones for either one is altered.

    The goal is to determine how multiple sites of acetylation (e.g. acK9 and acK56 on a single H3) change the thermodynamics of the nucleosomes and/or nucleosomal arrays. These changes may act synergistically to alter nucleosome and nucleosomal array stability. I hypothesize that this could explain why histone modifying enzymes are promiscuous and that sites modified by Rtt109 maybe specifically targeted to the first step in nucleosome assembly. I have already shown that H3K56 affects the deposition of the (H3-H4)2 tetramer on the DNA (the first step in nucleosome assembly) and I hypothesize that modifications such as H3K9 maybe involved in array destabilization.