Chandrasekharan Lab Research

Post-translational modifications of proteins function as epigenetic mechanisms and regulate protein homeostasis during many nuclear processes, including gene transcription and genome maintenance. Misregulation of protein-modifying enzymes is associated with a variety of solid and hematological cancers. Small molecule inhibitors of histone-modifying enzymes (the so called “epidrugs”) are a potential new class of therapeutics for treating cancers. The research mission of the Chandrasekharan Lab is to enhance our fundamental understanding of epigenetics and protein homeostasis mechanisms by combining structural, biochemical, and biophysical studies with functional genetics and omics-based approaches, and developing new epigenomics technologies. We also strive to translate the knowledge gained to better understand cancer pathogenesis and develop novel therapies. Specifically, our focus is to understand the enzymes and regulatory processes involved in the trans-histone crosstalk between histone H2B monoubiquitination and histone H3 lysine-4 (H3K4) and lysine-79 (K79) methylation and in protein homeostasis mechanisms.

Enzymes and regulatory factors involved in the dynamic regulation of H2B monoubiquitination or H3K4/K79 methylation are mutated or overexpressed in many different cancers. We employ a diverse set of classical and modern tools of chromatin biology or epigenetics, biochemistry and genetics, epigenomics, and structural biology, and we use both yeast and mammalian model systems to address the following fundamental and cancer-relevant questions:

1. How are the enzymes involved in the addition or removal of H2B monoubiquitination assembled, recruited, and regulated?
2. How does H2B monoubiquitination function in regulating various chromatin-based transactions, nuclear processes in general, and in cancer formation and progression?
3. What are the molecular switches within E2 ubiquitin-conjugating enzymes that govern their mono- versus poly-ubiquitination activities?
4. Is DOT1L H3K79 methyltransferase a viable therapeutic target in a subset of solid as well as hematological malignancies?
5. More broadly, can epigenetic modifiers and ubiquitin-conjugating enzymes act as druggable molecular vulnerabilities in cancers?