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

Academic Article

Abstract

  • 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.

    • Authors

    Published In

  • Developmental Cell  Journal

    • Keywords

  • ATF4, Myelin transcription factors, beta cell compensation, beta cell death, beta cell failure, diabetes, heat-shock proteins, post-transcriptional control, proliferation, stress response, Activating Transcription Factor 4, Animals, Cell Proliferation, DNA-Binding Proteins, Diabetes Mellitus, Female, Heat-Shock Proteins, Humans, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Stress, Physiological, Transcription Factors

    • Digital Object Identifier (doi)

    Author List

  • Hu R; Walker E; Huang C; Xu Y; Weng C; Erickson GE; Coldren A; Yang X; Brissova M; Kaverina I

    • Start Page

  • 390

    • End Page

  • 405.e10

    • Volume

  • 53

    • Issue

  • 4