UCLA

The chromatin architectural rearrangements that permit disease gene expression are just beginning to come to light. Distinct levels of chromatin organization are needed to maintain a healthy transcriptome, from the histone octamer that forms nucleosomes (the functional unit of chromatin) to chromosome territories that demarcate large swaths of the nucleus. An integrative picture of how each level of chromatin contributes towards healthy and disease gene expression has eluded us until chromosome conformation capture followed by high-throughput sequencing paved the way for deeper study of how chromatin features, such as significant chromosomal interactions, topologically associating domains, A/B compartmentalization, and enhancer-gene interactions all contribute towards gene regulation at a global scale. Heart failure is a syndrome characterized, in part, by a dysregulated gene expression program. We hypothesized that chromatin structure becomes deranged during heart failure, and we found this to be the case at multiple levels of chromatin organization. In addition, we found that healthy cardiac myocyte chromatin structure permits its organ-specific gene regulation program. This dissertation 1) summarizes the cardiovascular epigenetics work in the field; 2) reports our findings from our chromosome conformation studies in hearts that underwent pressure overload and those that underwent knockout of the chromatin structural protein CTCF to understand how pathology influences chromatin structure; and 3) reports our investigation into the chromatin architectural organization of healthy cardiac myocytes when compared to healthy liver, in an effort to understand how normal epigenomes are organized in three dimensions. These studies open avenues for future mechanistic cardiovascular epigenomics studies, as well as for exploration of therapeutic treatment of chromatin to promote healthier gene expression programs.