SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice

Kunhua Qin, Ning Zhang, Zhao Zhang, Michael Nipper, Zhenxin Zhu, Jake Leighton, Kexin Xu, Nicolas Musi, Pei Wang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalDiabetologia
DOIs
StateAccepted/In press - Jan 10 2018

Fingerprint

Insulin-Secreting Cells
Cell Survival
Histones
Insulin
Thioredoxins
Endocrine Cells
RNA Polymerase II
Acetylation
Streptozocin
Glucose
Lysine
Stem Cells
Gene Expression
Histone Deacetylases
Glucose Intolerance
Chromatin Immunoprecipitation
National Institutes of Health (U.S.)
Genetic Promoter Regions
Epigenomics
Knockout Mice

Keywords

  • Beta cell
  • Diabetes
  • H3K9Ac
  • Insulin secretion
  • SIRT6
  • TXNIP

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice. / Qin, Kunhua; Zhang, Ning; Zhang, Zhao; Nipper, Michael; Zhu, Zhenxin; Leighton, Jake; Xu, Kexin; Musi, Nicolas; Wang, Pei.

In: Diabetologia, 10.01.2018, p. 1-13.

Research output: Contribution to journalArticle

Qin, Kunhua ; Zhang, Ning ; Zhang, Zhao ; Nipper, Michael ; Zhu, Zhenxin ; Leighton, Jake ; Xu, Kexin ; Musi, Nicolas ; Wang, Pei. / SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice. In: Diabetologia. 2018 ; pp. 1-13.
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AU - Zhang, Zhao

AU - Nipper, Michael

AU - Zhu, Zhenxin

AU - Leighton, Jake

AU - Xu, Kexin

AU - Musi, Nicolas

AU - Wang, Pei

PY - 2018/1/10

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KW - H3K9Ac

KW - Insulin secretion

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