Post-translational modifications of proteins function as key epigenetic mechanisms that regulate protein homeostasis during nuclear processes such as gene transcription and genome maintenance. Misregulation of protein-modifying enzymes is frequently observed in solid and hematological malignancies. Small-molecule inhibitors of histone-modifying enzymes (“epidrugs”) are emerging as a promising class of therapeutics for treating cancer.

The Chandrasekharan Lab aims to deepen our fundamental understanding of epigenetic and protein homeostasis mechanisms and to translate this knowledge to improve cancer diagnosis and therapy. We combine structural, biochemical, and biophysical studies with functional genetics, omics-based approaches, and new epigenomics technologies. Our work focuses on the enzymes and regulatory pathways that control histone modifications (ubiquitination, methylation, and acetylation) and protein homeostasis.

Enzymes and regulatory factors that dynamically add or remove histone and other protein modifications are frequently mutated or aberrantly expressed in cancer. To dissect their functions and therapeutic potential, we employ a broad toolkit spanning chromatin biology/epigenetics, biochemistry, genetics, epigenomics, and structural biology, using both yeast and mammalian model systems. We address the following fundamental and cancer-relevant questions:

• How are enzymes that write or erase histone modifications assembled, recruited to chromatin, and regulated?
• How do histone modifications control chromatin-based processes during gene transcription and genome maintenance (including DNA repair)?
• What molecular switches within E2 ubiquitin-conjugating enzymes determine their mono- versus poly-ubiquitination activities?
• Are histone deacetylases HDAC1,2 and the H3K27 (EZH2) and H3K79 (DOT1L) methyltransferases viable therapeutic targets in subsets of solid and hematologic malignancies?
• How do altered histone modifications and epigenetic landscapes drive treatment resistance in leukemias, lymphomas, and glioblastomas?
• More broadly, can epigenetic modifiers and ubiquitin-conjugating enzymes be exploited as druggable molecular vulnerabilities in cancer?

Through this integrated approach, our long-term goal is to define mechanistic principles of epigenetic and protein homeostasis regulation and to leverage these insights to develop novel epigenetic-based cancer therapies.