Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function

Abstract

Manuscript SummaryAlthough stress response maintains cell function and survival under adverse conditions, over-activation of late-stage stress-gene effectors causes dysfunction and death. Here we show that the Myelin Transcription Factors (Myt 1, 2, and 3 TFs) prevent this over-activation. Co-inactivating 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 the putative enhancers of Atf4 and Hsps, whose over-expression in mouse β cells largely recapitulated the Myt mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in functional mouse and human β cells by metabolic stress but downregulated in those of type 2 diabetic islets that display ATF4 and HSP overactivation. Lastly, human MYT knockdown caused stress-gene over-activation and death in Endo-βH1 cells. These findings suggest that the Myt TFs restrict stressresponse to physiologically tolerable levels in mice and human.