498B Poster - 06. Regulation of gene expression
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Daniel Wilinski ¹; Tahrim Choudhury ^1,2; Monica Dus ¹

Affiliations:
1) Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor; 2) PREP Program, The University of Michigan, Ann Arbor

Keywords:
j. epigenetics; z. other (RNA methylation)

Epigenetic mechanisms control the proper function of beta cells and alterations in these pathways have been linked to the development of type 2 diabetes (T2D), a debilitating disease that affects ~30% of Americans and that has no cure. Among these epigenetic mechanisms, the methylation of N6-adenosines in mRNAs (m⁶A) –which controls mRNA stability, turnover, and translation– has recently emerged as a novel regulator of ß-cell biology. In mammals, many of the mRNAs important for insulin secretion and signaling, including the insulin mRNA, are marked with this epigenetic mark and many are hypomethylated in the ß-cells of people with T2D. Consistent with this, mutations in the methyltransferase enzymes impair insulin secretion and glucose homeostasis in mammals, suggesting that m⁶A directs essential aspects of ß-cells physiology. However, the molecular underpinnings of these phenotypes are not known and the precise function of this epigenetic pathway in the biology of the ß-cells remains largely a mystery. This lack of knowledge has hindered progress in uncovering the underlying causes of T2D and in developing new therapeutic interventions based on this epigenetic pathway. Here we propose to exploit the unique advantages of the fly D. melanogaster model to identify the molecular mechanisms through which the m⁶A pathway regulates the physiology of ß-cells. We discovered that in flies mutations in the m⁶A pathway give rise to similar cellular and physiological phenotypes measured in mammals. Our hypothesis is that this epigenetic pathway regulates the responses of the insulin cells to glucose and amino acids and the release of insulin. We are currently taking a multidisciplinary approach that includes molecular biology, genomics, ex vivo imaging, and metabolic measurements to test these hypotheses and will present the result of these experiments at the conference. Discovering how specific epigenetic mechanisms direct distinct ß-cells processes is relevant to public health because it will advance our understanding of the biology of these cells and the etiology of T2D.