Reprogramming of Chromatin States in cancer

The atypical nuclear structure in cancerous cells has been routinely used in the clinic to distinguish tumor cells from their normal counterparts for over 150 years, and recently genetic alterations of chromatin modulators, modifiers and effectors were reported in a wide array of cancer types. Dr. Lu’s previous work has demonstrated that cancer-associated chromatin-perturbing mutations are bona fide oncogenes and affect programs of stem cell self-renewal/differentiation. These studies evoked significant interests in the field to understand chromatin abnormality and (mis)regulation of gene expression in cancer. To date, such efforts have largely focused on small-scale genomic regions such as promoters, gene-bodies and enhancers. However, the fact that tumors often exhibit nuclear morphological changes that are microscopically visible suggests that large-scale remodeling of chromatin organization is common in cancer through mechanisms that remain poorly characterized. The current proposal employs innovative (epi)genomic and imaging technologies to define molecular mechanisms underlying aberrant division and organization of chromatin domains in cancer and their impact on transcriptional and lineage infidelity during tissue homeostasis and tumorigenesis. Since pathologic remodeling of chromatin states has been correlated with a variety of molecular and cellular hallmarks of cancer, the translational implication of expected results could be potentially far-reaching.