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

Qicheng Ni1, Jiajun Sun1, Yichen Wang1

  • 1Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Molecular Metabolism
|August 8, 2022
PubMed
Abstract

Insights

Mechanistic target of rapamycin complex 1 (mTORC1) regulates beta-cell maturation via epigenetic silencing. DNA methylation and H3K27me3 modification impair beta-cell function, but DNMT3A can restore it, impacting type 2 diabetes risk.

Area of Science:

  • Endocrinology
  • Epigenetics
  • Molecular Biology

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) is crucial for cell growth, linking nutrients to cellular functions.
  • mTORC1 signaling is essential for beta-cell functional maturation and identity maintenance.
  • The precise epigenetic mechanisms by which mTORC1 regulates beta-cell maturation remain incompletely understood.

Purpose of the Study:

  • To elucidate the underlying epigenetic mechanisms of mTORC1 in regulating beta-cell functional maturation.
  • To identify specific epigenetic modifications involved in beta-cell immaturity due to mTORC1 dysfunction.
  • To explore the potential of targeting these epigenetic mechanisms to restore beta-cell function.

Main Methods:

  • Analysis of epigenetic modifications (DNA methylation, H3K27me3) in immature beta-cells using Microarray, MeDIP-seq, and ATAC-seq.
  • Overexpression of DNMT3A in Raptor-deficient beta-cells to assess its impact on transcriptome and glucose-stimulated insulin secretion (GSIS).
  • Investigation of direct regulatory roles of Raptor in epigenetic modifier expression and gene marking.

Main Results:

  • Identified DNMT3A-dependent DNA methylation and PRC2-dependent H3K27me3 as key epigenetic silencing mechanisms in Raptor-deficient beta-cells.
  • DNMT3A overexpression partially reversed immature transcriptome patterns and restored GSIS in these cells.
  • Raptor was found to directly regulate PRC2/EED and H3K27me3 levels, marking immature beta-cell genes.

Conclusions:

  • This study reveals how mTORC1 integrates nutrient signals with epigenetic modifications (DNA methylation and H3K27me3) to control beta-cell identity and maturation.
  • These findings advance the understanding of beta-cell dysfunction in the context of nutrient availability and epigenetic regulation.
  • The identified mechanisms may have implications for the pathogenesis and therapeutic strategies for type 2 diabetes.
Keywords:
Dnmt3aEpigenetic regulationH3K27me3Type 2 diabetesmTORC1β-Cell

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