Epigenetic Regulation by Histone Modifiers in Development and Cancer

Project: Research project

Project Details

Description

The highly conserved COMPASS family of methylases implements histone H3 lysine 4 (H3K4) methylation, an epigenetic mark associated with transcriptionally active chromatin. Multiple genome-wide sequencing efforts reported that COMPASS subunits are frequently mutated across cancers and other diseases. Therefore, understanding COMPASS function will lend important mechanistic insights into disease pathogenesis, which is necessary for developing effective therapeutics. The H3K4 methylase Set1A is one of six COMPASS members identified in mammals, and possesses an enzymatic SET domain responsible for bulk H3K4 di- and trimethylation (H3K4me2/me3 respectively) across the genome. Previous studies demonstrated that loss of Set1A protein resulted in embryonic lethality and embryonic stem cell (ESC) proliferation defects, suggesting that Set1A is required for this process. In my recent publication, I discovered that the Set1A SET domain was surprisingly dispensable for ESC viability and self-renewal, although necessary for proper ESC differentiation. I have also shown that deleting Set1A’s SET domain neither alters the overall transcriptome nor perturbs bulk H3K4 methylation in Set1A∆SET vs. WT ESCs. Following on these findings, I will further elucidate the critical role of Set1A in ESC pluripotency and development during the F99 phase of training. The first objective during the F99 phase will examine the enzymatic function of Set1A by analyzing transcriptional and H3K4 methylation changes during early mouse development. The second objective is to conditionally deplete a known Set1A-specific interactor to determine the non-enzymatic role of Set1A in ESC pluripotency. The third question will explore the functional relationship between H3K4 methylation and transcription within the context of ESC pluripotency. This work will illuminate the basic functional significance of Set1A in stem cells and in development, which will elucidate its disease liability and ultimately facilitate treatment development.

During the K00 phase of training, I would like to study the epigenetic regulation of cancer progression, specifically aiming to leverage my knowledge of epigenetics to the fields of cancer stem cells (CSCs) and immuno-oncology. CSCs may be able to wield epigenetic alternations to attain gene signatures necessary for tumorigenesis, and cancer cells may also be exploiting epigenetic mechanisms to modify gene expression to escape immune surveillance, thereby contributing to tumor progression. The work to elucidate such mechanisms would provide invaluable insight into using combinations of epigenetic drugs and immunotherapies for remarkable efficacy.
StatusFinished
Effective start/end date9/7/188/31/20

Funding

  • National Cancer Institute (5F99CA234945-02)

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.