Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes

Axelsson, A.; Mahdi, Taman; Nenonen, Hannah; Singh, Tania; Hänzelmann, Sonja; Wendt, Anna; Bagge, Annika; Reinbothe, Thomas; Millstein, Joshua; Yang, Xia; Zhang, Bin; Gusmao, Eduardo Gade; Shu, Le; Szabat, Marta; Tang, Yunzhao; Wang, Jinling; Salö, Sofia; Eliasson, Lena; Artner, Isabella; Fex, Malin; Johnson, James D.; Wollheim, Claes B.; Derry, Jonathan M.J.; Mecham, Brig; Sartipy, Peter; Mulder, Hindrik; Costa, Ivan G.; Zhang, E; Rosengren, Anders H.

doi:10.1038/ncomms15652

Cited by 35 publications

(25 citation statements)

References 57 publications

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“…Previous studies have demonstrated that the HDAC inhibitor, VPA, increases insulin secretion in vivo (19,20). Consistent with these results, the present study revealed that VPA facilitated the secretion of insulin in two pancreatic β-cell lines.…”

Section: Discussionsupporting

confidence: 92%

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SIRT5 regulates pancreatic β‑cell proliferation and insulin secretion in type 2 diabetes

Fei

2018

Exp Ther Med

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Impaired insulin secretion and insulin resistance are the primary characteristics of type 2 diabetes (T2D). However, the mechanisms underlying insulin secretion failure have yet to be elucidated. The present study demonstrated that sirtuin 5 (SIRT5) is upregulated in patients with T2D and in pancreatic β-cell lines. It was also revealed that elevated SIRT5 expression is positively associated with age and blood glucose levels, and negatively associated with pancreatic and duodenal homeobox 1 (PDX1) expression. Colony formation and Cell Counting Kit-8 assays demonstrated that SIRT5 suppressed the proliferation of pancreatic β-cells . In addition, downregulation of SIRT5 promoted the secretion of insulin. Additionally, SIRT5 ectopic expression downregulated the expression of PDX1 and the inhibition of SIRT5 upregulated PDX1 expression. Chromatin immunoprecipitation assay analysis demonstrated that SIRT5 may regulate the transcription of PDX1 via H4K16 deacetylation. In conclusion, the results of the present study indicate that SIRT5 may serve an important role in the pathogenesis of T2D, and may present a novel therapeutic target for the treatment of patients with T2D.

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Section: Discussionsupporting

confidence: 92%

“…5B). The results therefore suggest that VPA may be a novel therapy for T2D, which is consistent with the results of previous studies (19,20).…”

Section: Sirt5 Protein Expression -----------------------------------supporting

confidence: 92%

SIRT5 regulates pancreatic β‑cell proliferation and insulin secretion in type 2 diabetes

Fei

2018

Exp Ther Med

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“…Intriguingly, dysfunctional β cells from T2D human donors had significantly reduced MYT3 and upregulated stress-gene transcription. This latter point, supported by our RePACT-based single-cell RNAseq, is consistent with results from conventional gene expression analyses, which showed down-regulation of MYT3 (Axelsson et al, 2017) and up-regulation of ATF1, ATF3, Hsp40, 70, 90, and 105 (Bugliani et al, 2013;Gunton et al, 2005;Hartman et al, 2004;Marselli et al, 2010;Segerstolpe et al, 2016).…”

Section: Bidirectional Connections Between Myt Tfs and Stress-responssupporting

confidence: 90%

Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function

Walker

et al. 2019

Preprint

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Manuscript SummaryAlthough stress response maintains cell function and survival under adverse conditions, over-activation of late-stage stress-gene effectors causes dysfunction and death. Here we show that the Myelin Transcription Factors (Myt 1, 2, and 3 TFs) prevent this over-activation. Co-inactivating Myt TFs in mouse pancreatic progenitors compromised postnatal β-cell function, proliferation, and survival, preceded by upregulation of late-stage stress-response genes Activating Transcription Factors (e.g., Atf4) and Heat Shock Proteins (Hsps). Myt1 binds the putative enhancers of Atf4 and Hsps, whose over-expression in mouse β cells largely recapitulated the Myt mutant phenotypes. Moreover, Myt(MYT)-TF levels were upregulated in functional mouse and human β cells by metabolic stress but downregulated in those of type 2 diabetic islets that display ATF4 and HSP overactivation. Lastly, human MYT knockdown caused stress-gene over-activation and death in Endo-βH1 cells. These findings suggest that the Myt TFs restrict stressresponse to physiologically tolerable levels in mice and human.

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“…Overall, these results help further understanding of the mechanisms by which ROIT regulates beta cell function. Herein, we found some novel lncRNAs, such as lncRNA-SOX5 and lncRNA-PTPRD by RNA-seq assays, which might play a crucial role in human beta cell function based on previous findings [47,48]. However, whether these lncRNAs are able to regulate mouse beta cell function is unclear.…”

Section: Discussionmentioning

confidence: 90%

Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation

et al. 2020

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Aims/hypothesis Although obesity is a predisposing factor for pancreatic beta cell dysfunction, the mechanisms underlying its negative effect on insulin-secreting cells is still poorly understood. The aim of this study was to identify islet long non-coding RNAs (lncRNAs) involved in obesity-mediated beta cell dysfunction. Methods RNA sequencing was performed to analyse the islets of high-fat diet (HFD)-fed mice and those of normal chow-fed mice (NCD). The function in beta cells of the selected lncRNA 1810019D21Rik (referred to in this paper as ROIT [regulator of insulin transcription]) was assessed after its overexpression or knockdown in MIN6 cells and primary islet cells, as well as in siRNA-treated mice. Then, RNA pull-down, RNA immunoprecipitation, coimmunoprecipitation and bisulphite sequencing were performed to investigate the mechanism of ROIT regulation of islet function.Results ROIT was dramatically downregulated in the islets of the obese mice, as well as in the sera of obese donors with type 2 diabetes, and was suppressed by HNF1B. Overexpression of ROIT in MIN6 cells and islets led to improved glucose homeostasis and insulin transcription. Investigation of the mechanism involved showed that ROIT bound to DNA methyltransferase 3a and caused its degradation through the ubiquitin proteasome pathway, which blocked the methylation of the Nkx6.1 promoter. Conclusions/interpretation These findings functionally suggest a novel link between obesity and beta cell dysfunction via ROIT. Elucidating a precise mechanism for the effect of obesity on lncRNA expression will broaden our understanding of the pathophysiological development of diabetes and facilitate the design of better tools for diabetes prevention and treatment. Data availability The raw RNA sequencing data are available from the NCBI Gene Expression Omnibus (GEO series accession number GSE139991).

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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes

Cited by 35 publications

References 57 publications

SIRT5 regulates pancreatic β‑cell proliferation and insulin secretion in type 2 diabetes

SIRT5 regulates pancreatic β‑cell proliferation and insulin secretion in type 2 diabetes

Myt Transcription Factors prevent stress-response gene over-activation to enable postnatal pancreatic β cell proliferation and function

Obesity-induced reduced expression of the lncRNA ROIT impairs insulin transcription by downregulation of Nkx6.1 methylation

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