351-OR: Role of Mef2a in Beta-Cell Differentiation and Function during ER Stress

Introduction and Objective: Short-term ER stress engages adaptative unfolded protein response (UPR) associated with higher β-cell function and proliferation. Chronic ER stress or decompensated UPR leads to loss of b-cell identity and function and causes death, ultimately leading to diabetes. The objective of this study was to identify genes and pathways responsible for this UPR switch from adaptive to decompensated.

Methods: To define UPR states, we performed bulk RNA seq using three different models: 1) Mild UPR (High glucose-increased β-cell proliferation, maturity, and function), 2) Medium UPR (Atf6 activation-increased β-cell proliferation and loss of maturity but no death), 3) Decompensated UPR (Grp78 knockdown- no change in β-cell proliferation, increased de-differentiation, and death).

Results: We performed bulk RNA sequencing on mouse primary islet cells. Our RNA seq data identified myocyte enhancer factor 2a (Mef2a) as a novel transcription factor dysregulated during decompensated ER stress. Mef2a is a Ca²⁺-regulated gene which senses Ca²⁺ changes in the cells. Our data shows that overexpression of Mef2a causes β-cell de-differentiation, resulting in the loss of insulin secretion. ER stress caused by Thapsigargin (Tg) and Tunicamycin (Tm) increased Mef2a activity, β-cell de-differentiation, and loss of function. Knockdown of Mef2a partially and fully rescued β-cell de-differentiation and loss of function caused by Tg and Tm, respectively.

Conclusion: Mef2a could act as a molecular switch sensing Ca²⁺ changes during continuous β-cell ER stress, leading to its hyperactivity. This study shows that Mef2a knockdown rescued the loss of β-cell identity and function under decompensated ER stress.