Glucose stimulates microRNA-199 expression in murine pancreatic β-cells

Werneck-de-Castro, João Pedro; Blandino-Rosano, X. Manuel; Hilfiker‐Kleiner, Denise; Bernal-Mizrachi, Ernesto

doi:10.1074/jbc.ra119.010356

Cited by 10 publications

(5 citation statements)

References 49 publications

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“…In previous work, the miR-216a knockout mouse was reported to have defects in insulin secretion in the context of chronic high-fat diet (77), and miR-25 has been described as a negative regulator of insulin synthesis in INS-1 cells, a rat beta cell line (64). As another example, we show that miR-199b-5p is associated with T2D status, consistent with a previous study in murine beta cells where miR-199b-5p was shown to be highly responsive to glucose stimulation (78). We also find that miR-21-5p is strongly associated with T2D status.…”

Section: Discussionsupporting

confidence: 92%

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Taylor¹,

Hung

Narisu³

et al. 2022

Preprint

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Genetic studies have identified ≥240 loci associated with risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, representing the largest sequencing-based analysis of miRNA expression in human islets to date. We characterize the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression (miRNA-eQTLs). We find (i) 81 heritable miRNAs, primarily regulated by trans-acting genetic effects, and (ii) 5 miRNA-eQTLs. We also use several different strategies to identify T2D-associated miRNAs. First, we colocalize miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersect miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and find 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we perform differential expression analysis and identify 13 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

show abstract

Section: Discussionsupporting

confidence: 92%

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Taylor¹,

Hung

Narisu³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In previous work, the miR-216a knockout mouse was reported to have defects in insulin secretion in the context of chronic high-fat diet ( 90 ), and miR-25 has been described as a negative regulator of insulin synthesis in INS-1 cells, a rat insulinoma cell line ( 75 ). As another example, we show that miR-199b-5p is associated with T2D status, consistent with a previous study in murine beta cells where miR-199b-5p was shown to be highly responsive to glucose stimulation ( 91 ). We also find that miR-21-5p is strongly associated with T2D status.…”

Section: Discussionsupporting

confidence: 92%

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Taylor

Hung

Narisu

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans- acting genetic components and mapping cis -acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans -acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

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“…As miR-199 was reported to be dysregulated in cancer from all these organs [35][36][37] , the corresponding mechanisms responsible for the dysregulation of miR-199 may be also different. Moreover, in mouse islets, miR-199a-3p is from both miR-199a-1 and miR-199a-2, but not miR-199b, and the pri-miR-199a-1 is about 30% more than pri-miR-199a-2, whose expression are regulated by glucose metabolism and calcium influx 38 . Thus, why miR-199-3p is expressed from different gene locus in different organs and the underlying biological significance are interesting topics, which still need further exploration.…”

Section: Discussionmentioning

confidence: 92%

microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4

Zhou

Zhang

et al. 2020

Oncogenesis

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Hepatic apoptosis and the initiated liver inflammation play the initial roles in inflammation-induced hepatocarcinogenesis. Molecular mechanisms underlying the regulation of hepatocyte apoptosis and their roles in hepatocarcinogenesis have attracted much attention. A set of microRNAs (miRNAs) have been determined to be dysregulated in hepatocellular carcinoma (HCC) and participated in cancer progression, however, the roles of these dysregulated miRNAs in carcinogenesis are still poorly understood. We previously analyzed the dysregulated miRNAs in HCC using high-throughput sequencing, and found that miR-199a/b-3p was abundantly expressed in human normal liver while markedly decreased in HCC, which promotes HCC progression. Whether miR-199a/b-3p participates in HCC carcinogenesis is still unknown up to now. Hence, we focused on the role and mechanism of miR-199a/b-3p in hepatocarcinogenesis in this study. Hepatic miR-199a/b-3p was determined to be expressed by miR-199a-2 gene in mice, and we constructed miR-199a-2 knockout and hepatocyte-specific miR-199a-2 knockout mice. Diethylnitrosamine (DEN)-induced hepatocarcinogenesis were markedly increased by hepatocyte-specific miR-199a-3p knockout, which is mediated by the enhanced hepatocyte apoptosis and hepatic injury by DEN administration. In acetaminophen (APAP)-induced acute hepatic injury model, hepatocyte-specific miR-199a-3p knockout also aggravated hepatic apoptosis. By proteomic screening and reporter gene validation, we identified and verified that hepatic programed cell death 4 (PDCD4), which promotes apoptosis, was directly targeted by miR-199a-3p. Furthermore, we confirmed that miR-199a-3p-suppressed hepatocyte apoptosis and hepatic injury by targeting and suppressing PDCD4. Thus, hepatic miR-199a-3p inhibits hepatocyte apoptosis and hepatocarcinogenesis, and decreased miR-199a-3p in hepatocytes may aggravate hepatic injury and HCC development.

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Glucose stimulates microRNA-199 expression in murine pancreatic β-cells

Cited by 10 publications

References 49 publications

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4

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