Long non-coding RNAs as novel players in β cell function and type 1 diabetes

Mirza, Aashiq H.; Kaur, Simranjeet; Pociot, Flemming

doi:10.1186/s40246-017-0113-7

Cited by 47 publications

(41 citation statements)

References 99 publications

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“…They also affect DNA methylation, the chromatin landscape, and subsequent gene silencing or activation [8][9][10]. Abnormal expression of lncRNAs has been associated with a variety of human diseases, including diabetes [11]. Recent studies have identified thousands of lncRNAs in human pancreatic beta cells as well as in mouse pancreatic islet cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…We recently used such an approach to construct protein interaction networks from all genes located in non-HLA loci associated with T1D combined with tissue-specic transcriptomic data to identify significantly regulated network. 37 , 82, 83, 84, 85 . This indicates that protein networks can add biological context to candidate genes identified through GWAS.…”

Section: New Insights Arising From Gwasmentioning

confidence: 99%

“…84 Nevertheless, it is foreseen that a more in-depth understanding of ncRNAs may in near future open new strategies for diagnostics, classification and personalized therapeutic regiments in T1D and other immune-mediated diseases. 85 …”

Section: New Insights Arising From Gwasmentioning

confidence: 99%

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Type 1 diabetes genome‐wide association studies: not to be lost in translation

Pociot

2017

Clin & Trans Imm

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Genetic studies have identified >60 loci associated with the risk of developing type 1 diabetes (T1D). The vast majority of these are identified by genome-wide association studies (GWAS) using large case–control cohorts of European ancestry. More than 80% of the heritability of T1D can be explained by GWAS data in this population group. However, with few exceptions, their individual contribution to T1D risk is low and understanding their function in disease biology remains a huge challenge. GWAS on its own does not inform us in detail on disease mechanisms, but the combination of GWAS data with other omics-data is beginning to advance our understanding of T1D etiology and pathogenesis. Current knowledge supports the notion that genetic variation in both pancreatic β cells and in immune cells is central in mediating T1D risk. Advances, perspectives and limitations of GWAS are discussed in this review.

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“…Long noncoding RNAs (lncRNAs) constitute a group of RNA molecules more than 200 nucleotides long that are not translated into proteins. LncRNAs are associated with different diseases (9,10), including diabetes (11)(12)(13)(14), and are known to orchestrate biologically relevant (15) signaling networks that regulate cell-and tissue-specific gene expression (16)(17)(18). Recent studies have examined lncRNAs in human pancreatic islets (19)(20)(21)(22)(23); one of these landmark studies (22) uncovered human islet cell lncRNAs that are associated with key pancreatic transcription factors.…”

Section: Introductionmentioning

confidence: 99%