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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.

SUBMITTER: Wang RR

PROVIDER: S-EPMC9166293 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming.

Wang Ruo-Ran RR Qiu Xinyuan X Pan Ran R Fu Hongxing H Zhang Ziyin Z Wang Qintao Q Chen Haide H Wu Qing-Qian QQ Pan Xiaowen X Zhou Yanping Y Shan Pengfei P Wang Shusen S Guo Guoji G Zheng Min M Zhu Lingyun L Meng Zhuo-Xian ZX

The Journal of experimental medicine 20220602 7

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 alt ...[more]

PMID: 35652891

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Project description:AIMS/HYPOTHESIS:Better understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase sirtuin 6 (SIRT6) in beta cell development and homeostasis. METHODS:Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated using the Cre-loxP system. Mice were assayed for islet morphology, glucose tolerance, glucose-stimulated insulin secretion and susceptibility to streptozotocin. Transcriptional regulatory functions of SIRT6 in primary islets were evaluated by RNA-Seq analysis. Reverse transcription-quantitative (RT-q)PCR and immunoblot were used to verify and investigate the gene expression changes. Chromatin occupancies of SIRT6, H3K9Ac, H3K56Ac and active RNA polymerase II were evaluated by chromatin immunoprecipitation. RESULTS:Deletion of Sirt6 in pancreatic endocrine progenitor cells did not affect endocrine morphology, beta cell mass or insulin production but did result in glucose intolerance and defective glucose-stimulated insulin secretion in mice. Conditional deletion of Sirt6 in adult beta cells reproduced the insulin secretion defect. Loss of Sirt6 resulted in aberrant upregulation of thioredoxin-interacting protein (TXNIP) in beta cells. SIRT6 deficiency led to increased acetylation of histone H3 lysine residue at 9 (H3K9Ac), acetylation of histone H3 lysine residue at 56 (H3K56Ac) and active RNA polymerase II at the promoter region of Txnip. SIRT6-deficient beta cells exhibited a time-dependent increase in H3K9Ac, H3K56Ac and TXNIP levels. Finally, beta cell-specific SIRT6-deficient mice showed increased sensitivity to streptozotocin. CONCLUSIONS/INTERPRETATION:Our results reveal that SIRT6 suppresses Txnip expression in beta cells via deacetylation of histone H3 and plays a critical role in maintaining beta cell function and viability. DATA AVAILABILITY:Sequence data have been deposited in the National Institutes of Health (NIH) Gene Expression Omnibus (GEO) with the accession code GSE104161.

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Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming.

Publications

Dietary intervention preserves β cell function in mice through CTCF-mediated transcriptional reprogramming.

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