Description:

The Simpson Querrey Institute for Epigenetics presents:

Yael David, PhD

Associate Member, Chemical Biology Program
Memorial Sloan Kettering, NY

"Thinking Outside the Chromosome: Interrogating Epigenetic Mechanisms in Non-Canonical Chromatin Species"

Abstract:

Epigenetic regulation governs DNA-templated processes, playing a pivotal role in determining cell phenotype and fate. Disruption of epigenetic cascades is implicated in various disease states, notably cancer. Many of these pathological conditions involve significant chromosomal rearrangements, leading to the formation of non-canonical chromatin structures present in primary nuclei or enclosed in spatially distinct micronuclei. Recently, we adopted a mechanistic approach to explore the properties of these unique non-chromosomal structures, unveiling substantial epigenetic contributions to their regulation. 

Our investigations revealed that micronuclei undergo altered epigenetic landscapes upon departure from the nucleus. Importantly, they retain these epigenetic 'scars' upon reintegrating into primary nuclei, contributing to epigenetic reprogramming and heterogeneity in cancer. Shifting our focus, we delved into the covalently closed circular DNA (cccDNA) minichromosome of the Hepatitis B Virus (HBV). This minichromosome, formed from viral DNA and human histones following infection, undergoes chromatinization, driving the expression of the key viral oncogene, HBx, and facilitating viral infection. Our elucidation of this novel mechanism has allowed us to disrupt infection by inhibiting histone remodeling, presenting a potential first-in-class therapy for HBV.

In my seminar, I will elaborate on how these exciting findings underscore the critical role of chromatin in biomedical events. Additionally, I will discuss how a fundamental understanding of these processes can pave the way for identifying new therapeutic avenues.