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

By Ruiying Hu, Emily Walker, Yanwen Xu, Chen Huang, Chen Weng, Gillian E. Erickson, Anastasia Golovin, Xiaodun Yang, Marcella Brissova, Appakalai N. Balamurugan, Christopher V. E. Wright, Yan Li, Roland Stein, Guoqiang Gu

Posted 18 Sep 2019
bioRxiv DOI: 10.1101/773846

Although 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 over-activation. Lastly, human MYT knockdown caused stress-gene over-activation and death in Endo-βH1 cells. These findings suggest that the Myt TFs restrict stress-response to physiologically tolerable levels in mice and human.

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