Abstract SY03-03: Thinking outside the chromosome: Interrogating epigenetic mechanisms in noncanonical chromatin species

Abstract The epigenetic regulation of DNA-templated processes is intricately tied to numerous events that determine cell phenotype and fate. The abrogation of epigenetic cascades drives various disease states, including cancer. Many of these pathological phenomena involve major chromosomal arrangements that can include the generation of non-canonical chromatin structures existing in the primary nuclei or encapsulated in spatially distinct micronuclei. Recently, we undertook a mechanistic approach to investigate the properties of unique non-chromosomal structures, revealing significant epigenetic contributions to their regulation. We found that micronuclei, the result of chromosomal instability in cancer, assume altered epigenetic landscapes upon departure from the nucleus. Moreover, chromosomes sequestered in micronuclei retain the epigenetic "scars" after reintegration into the primary nucleus, contributing to epigenetic reprogramming and heterogeneity in cancer. Additionally, we turned our attention to the Hepatitis B Virus' (HBV) covalently closed circular DNA (cccDNA) minichromosome, which forms from viral DNA and human histones following infection. We found that chromatinization drives the expression of the key viral oncogene, HBx, and thus promotes viral infection. Elucidating this new mechanism enabled us to halt infection by inhibiting histone remodeling, creating a potential first-in-class therapy for HBV. These exciting findings demonstrate the key role of chromatin in biomedical events and how a fundamental understanding of these processes can lead to the identification of new therapeutic avenues. Citation Format: Yael David. Thinking outside the chromosome: Interrogating epigenetic mechanisms in noncanonical chromatin species abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr SY03-03.