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

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 (3-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 (3-cell functional maturation.Methods: We performed Microarray, MeDIP-seq and ATAC-seq analysis to explore the abnormal epigenetic regulation in 8-week-old immature (3RapKO islets. Moreover, DNMT3A was overexpressed in (3RapKO 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 (3-cell. Overexpression of DNMT3A partially reversed the immature transcriptome pattern and restored the impaired GSIS in Raptor-deficient (3-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 (3-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 (3-cell identity and functional maturation, and therefore may impact the disease risk of type 2 diabetes.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study reveals that DNMT3A-dependent DNA methylation and PRC2-dependent H3K27me3 modification are major epigenetic silencing mechanisms responsible for the functional immaturity of Raptor-deficient β-cells. Overexpression of DNMT3A partially reverses the immature transcriptome pattern and restores impaired GSIS in Raptor-deficient β-cells. Additionally, Raptor directly regulates PRC2/EED and H3K27me3 expression levels, as well as a group of immature genes marked with H3K27me3.