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

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 Hsp s, 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. • Myt TFs repress late-stage stress-response genes in mouse and human β cells • Atf4 and Hsps are major Myt TF target genes required for postnatal β cell fitness • Metabolic stress induces nuclear Myt TF during mouse/human β cell compensation • MYT TFs are inactivated in dysfunctional human T2D β cells Precisely regulating stress response is necessary for cell function and survival under stressful conditions. In this study, Hu et al. show that a family of myelin TFs, which themselves are induced by cellular stress, directly repress the transcription of late-stage stress-response genes to facilitate postnatal islet β cell proliferation, function, and survival. [ABSTRACT FROM AUTHOR]