In this thesis, we leverage epigenetic datasets that provide a limited view of the epigenome to understand changes in transcriptional activity across a diverse set of cellular contexts. It is often the case that we would like to learn about an epigenome that is partially characterized by different types of experiments. In our case, the epigenome is often partially characterized using assays that measure chromatin accessibility. In the European fable of Stone Soup, a hungry traveler convinces a village to give them ingredients to make soup; however, all the traveler has available to them are stones. Thus, the stones provide a basis for the soup, as it brings in other crucial ingredients to design a hearty meal. In this thesis, we leverage chromatin accessibility as our stone: the primary ingredient that we leverage to gather a more complete view of the epigenome.
In the first part of this work, we explore methods designed to increase our understanding of the epigenome, primarily through the identification of genomic locations that are crucial to regulatory activity, including binding sites of transcription factors and modification of histone tails. In particular, we introduce two methods designed to predict such epigenetic events. While the first of these methods is designed to predict epigenetic events from DNA sequence alone, the second method improves upon existing methodology to predict epigenetic events in novel cellular contexts using chromatin accessibility as the primary indicator of context specificity.
In the second part of this work, we leverage chromatin accessibility, as well as additional transcriptomic epigenetic information, to characterize changes between cellular contexts for various applications. In the first application, we leverage chromatin accessibility and transcriptomics to understand how CD8(+) T cells change after reprogramming cells to a pluripotent state, and how maintenance of the T cell phenotype can ultimately effect outcomes for cancer immunotherapy. Finally, we explore the role of the transcription factor, MORC3, in modulation of the accessible genome in the innate immune system. Together, these applications demonstrate how chromatin accessibility can be leveraged to characterize changes in regulatory activity and gain a more complete understanding of the epigenome.
