Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming
- PMID: 35652891
- PMCID: PMC9166293
- DOI: 10.1084/jem.20211779
Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming
Abstract
Pancreatic β cell plasticity is the primary determinant of disease progression and remission of type 2 diabetes (T2D). However, the dynamic nature of β cell adaptation remains elusive. Here, we establish a mouse model exhibiting the compensation-to-decompensation adaptation of β cell function in response to increasing duration of high-fat diet (HFD) feeding. Comprehensive islet functional and transcriptome analyses reveal a dynamic orchestration of transcriptional networks featuring temporal alteration of chromatin remodeling. Interestingly, prediabetic dietary intervention completely rescues β cell dysfunction, accompanied by a remarkable reversal of HFD-induced reprogramming of islet chromatin accessibility and transcriptome. Mechanistically, ATAC-based motif analysis identifies CTCF as the top candidate driving dietary intervention-induced preservation of β cell function. CTCF expression is markedly decreased in β cells from obese and diabetic mice and humans. Both dietary intervention and AAV-mediated restoration of CTCF expression ameliorate β cell dysfunction ex vivo and in vivo, through transducing the lipid toxicity and inflammatory signals to transcriptional reprogramming of genes critical for β cell glucose metabolism and stress response.
© 2022 Wang et al.
Conflict of interest statement
Disclosures: The authors declare no competing interests exist.
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Comments on 'Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming'.J Mol Cell Biol. 2022 Sep 27;14(7):mjac043. doi: 10.1093/jmcb/mjac043. J Mol Cell Biol. 2022. PMID: 35916443 Free PMC article. No abstract available.
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