Understanding the molecular and functional consequences of epigenome dynamics in cell fate, aging, and disease

DNA replication plays an important part in allowing cells to proliferate and develop into complex tissues. The advent of multicellular organisms, however, has been theorized to be intertwined with the tradeoff of aging and disease. These events are highly associated with drastic changes in gene expression across a cell population, often regulated by the epigenome. The set of heritable modifications that make up the epigenetic landscape are known to be altered by cell fate, aging, and disease. However, the dynamic processes by which the changes in the epigenome, and subsequently transcriptome, lead to these modified cell states are not clearly understood. In this dissertation, we demonstrate that DNA replication leads to a transient window of epigenetic entropy, providing the first evidence of a molecular link between cell fate, aging, and disease. In order to elucidate this link, we made use of replication-associated bisulfite sequencing (Repli-BS) and replication-associated assay for transposase-accessible chromatin sequencing (Repli-ATAC) datasets in human embryonic stem cells (hESCs). Our results suggest that the temporality of this window for both the chromatin architecture and DNA methylation differs across the genome. Specifically, we identified that the regions with the most prolonged window of epigenetic entropy are located at regulatory features, associate with expression variability, and are susceptible to age- and disease-related epigenetic drift. Additionally, this dissertation explores the impact of individual LMNA mutations on the epigenome that lead to unique disease outcomes of dilated cardiomyopathy (DCM) and brachydactyly using patient-derived fibroblasts and induced pluripotent stem cells (iPSCs). Analyses combining multiple epigenetic features and transcriptomic data suggest that differentially methylated regions (DMRs) are associated with the misregulation of regulatory elements, and that, in combination with chromatin remodeling, could lead to gene dysregulation ending in DCM. Ultimately, our results provide evidence that somatic and reprogrammed patient cells could serve as models to understand the mechanism behind which disease-related regulatory abnormalities lead to laminopathies like DCM and brachydactyly