mTORC1 is required for epigenetic silencing during β-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 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.