The overarching theme of my independent research will be to study the role of histone ubiquitylation in epigenetics, with a focus on the link between histone ubiquitylation and DNA methylation (DNAme). The role of ubiquitin conjugation in regulating protein function, degradation, and localization has long been established; however, histone ubiquitylation is emerging as a critical epigenetic mark. While the functional consequences of ubiquitylation to a few specific lysines on histones are known, the regulatory role of ubiquitin in epigenetics is underappreciated, highlighted by the number of sites of histone ubiquitylation with unknown functions identified with mass spectrometry.
Recent studies performed by myself (Harrison et al. eLife 2016) and others have identified a link between histone ubiquitylation and DNAme. DNAme is a heritable epigenetic modification occurring on CpG dinucleotides and has been extensively studied as a repressor of gene expression. Changes in DNAme patterns are required for development and differentiation and are one of the hallmarks of cancer. Indeed, carcinogenesis is accompanied by a reduction in bulk DNAme and aberrant de novo methylation. However detailed knowledge about how DNAme patterns are established and degenerate in disease is lacking. Therefore, mechanistic understanding of how histone ubiquitylation regulates DNAme will provide insight into development and disease and may provide avenues for novel therapeutics.
