mTORC1 is required for epigenetic silencing during β-cell functional maturation

Mol Metab. 2022 Oct:64:101559. doi: 10.1016/j.molmet.2022.101559. Epub 2022 Aug 5.

Abstract

Objective: The mechanistic target of rapamycin complex 1 (mTORC1) is a key molecule that links nutrients, hormones, and growth factors to cell growth/function. Our previous studies have shown that mTORC1 is required for β-cell functional maturation and identity maintenance; however, the underlying mechanism is not fully understood. This work aimed to understand the underlying epigenetic mechanisms of mTORC1 in regulating β-cell functional maturation.

Methods: We performed Microarray, MeDIP-seq and ATAC-seq analysis to explore the abnormal epigenetic regulation in 8-week-old immature βRapKO islets. Moreover, DNMT3A was overexpressed in βRapKO islets by lentivirus, and the transcriptome changes and GSIS function were analyzed.

Results: We identified two major epigenetic silencing mechanisms, DNMT3A-dependent DNA methylation and PRC2-dependent H3K27me3 modification, which are responsible for functional immaturity of Raptor-deficient β-cell. Overexpression of DNMT3A partially reversed the immature transcriptome pattern and restored the impaired GSIS in Raptor-deficient β-cells. Moreover, we found that Raptor directly regulated PRC2/EED and H3K27me3 expression levels, as well as a group of immature genes marked with H3K27me3. Combined with ATAC-seq, MeDIP-seq and ChIP-seq, we identified β-cell immature genes with either DNA methylation and/or H3K27me3 modification.

Conclusion: The present study advances our understanding of the nutrient sensor mTORC1, by integrating environmental nutrient supply and epigenetic modification, i.e., DNMT3A-mediated DNA methylation and PRC2-mediated histone methylation in regulating β-cell identity and functional maturation, and therefore may impact the disease risk of type 2 diabetes.

Keywords: Dnmt3a; Epigenetic regulation; H3K27me3; Type 2 diabetes; mTORC1; β-Cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Epigenesis, Genetic* / genetics
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism

Substances

  • Histones
  • Mechanistic Target of Rapamycin Complex 1