Elements with increased MPRA activity under ER stress were enriched for motifs of TFs that mediate transcriptional responses to uncompensated ER stress and whose activity and/or abundance is increased in T2D patient islets54, such as ATF4 and DDIT3/CHOP15,55–57, as well as factors linked to pathophysiologic epigenetic changes in the beta cells of diet-induced obese mice (Mef2a58) and beta-cell senescence (THRa59) (Fig. 1e; Supplementary Data 2). Here, ATF4 is linked to type 2 diabetes mellitus.