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Myt Transcription Factors Prevent Stress-Response Gene Overactivation to Enable Postnatal Pancreatic β Cell Proliferation, Function, and Survival


Hu R , Walker E , Huang C , Xu Y , Weng C , Erickson GE , Coldren A , Yang X , Brissova M , Kaverina I , Appakalai BN , Wright CVE , Li Y , Stein R , Gu G , . Developmental cell. 2020 4 30; 53(4). 390-405.e10


Although cellular stress response is important for maintaining function and survival, overactivation of late-stage stress effectors cause dysfunction and death. We show that the myelin transcription factors (TFs) Myt1 (Nzf2), Myt2 (Myt1l, Nztf1, and Png-1), and Myt3 (St18 and Nzf3) prevent such overactivation in islet β cells. Thus, we found that co-inactivating the Myt TFs in mouse pancreatic progenitors compromised postnatal β cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genes activating transcription factors (e.g., Atf4) and heat-shock proteins (Hsps). Myt1 binds putative enhancers of Atf4 and Hsps, whose overexpression largely recapitulated the Myt-mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in mouse and human β cells during metabolic stress-induced compensation but downregulated in dysfunctional type 2 diabetic (T2D) human β cells. Lastly, MYT knockdown caused stress-gene overactivation and death in human EndoC-βH1 cells. These findings suggest that Myt TFs are essential restrictors of stress-response overactivity.