CHD4-MEDIATED TRANSCRIPTIONAL REGULATION OF PANCREATIC BETA CELL DEVELOPMENT AND FUNCTION

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PROJECT SUMMARY / ABSTRACT Diabetes is a global epidemic that is expected to become even more severe. Although there are treatment options, such as exogenous insulin, one of the most promising long-term treatments is transplanting donor islets into diabetic patients. While this treatment can allow patients to maintain normal blood glucose levels for extended periods of time, there is an extreme lack in the amount of viable donor islets for transplantation. To combat the lack of suitable donor islets, researchers have begun to differentiate human pluripotent stem cells (hPSCs) into β-like cells that respond to glucose by secreting insulin, with the hopes of creating a limitless supply of transplantable pancreatic β cells. This approach has been somewhat successful; however, the current differentiation protocols lack the ability to make pure populations of β cells and often result in immature β cells and polyhormonal cell populations. More complete knowledge of the transcriptional networks and associated cofactors required in the differentiation and function of pancreatic β cells is needed to supplement the current hPSC differentiation protocols and provide the information required for better diabetes treatment options. One such cofactor is the chromodomain helicase DNA-binding protein 4 (CHD4). CHD4 is the motor protein of the nucleosome remodeling and deacetylase (NuRD) complex and, along with histone deacetylase 1 and 2 (HDAC1 and 2), CHD4 creates condensed chromatin states, thereby repressing genes. Preliminary data has shown that CHD4 interacts with essential transcription factors in pancreatic β cells. Furthermore, my preliminary data shows that the loss of CHD4 in the β cells of mice causes hyperglycemia along with glucose intolerance. This suggests that CHD4 is a necessary transcriptional cofactor in the function of β cells. A better understanding of the role CHD4 plays in the development and function of pancreatic β cells could provide additional information to facilitate the directed differentiation of β cells from hPSCs in vitro. In this proposal, using both in vivo and in vitro experiments, I will determine the role and mechanism of CHD4 in the development and function of pancreatic β cells.