Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion

Ofori, Jones K.; Karagiannopoulos, Alexandros; Nagao, Mototsugu; Westholm, Efraim; Ramadan, Shaima; Wendt, Anna; Esguerra, Jonathan Ls; Eliasson, Lena

doi:10.2337/db21-0077

Cited by 22 publications

(33 citation statements)

References 34 publications

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“…However, the bulk of these studies are in model systems (e.g., animal models, cell lines), so our knowledge of miRNAs in human pancreatic islets (HPIs) remains limited. To date, most studies examining miRNA expression in HPIs have tested only a small number of miRNAs (25)(26)(27)(28). Of the two more comprehensive sequencing-based studies of HPI miRNAs (29,30), both have been limited in sample size (n≤7).…”

Section: Introductionmentioning

confidence: 99%

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.

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Section: Introductionmentioning

confidence: 99%

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

“…However, the bulk of these studies are in model systems (e.g., animal models, cell lines), so our knowledge of miRNAs in human pancreatic islets (HPIs) remains limited. To date, most studies examining miRNA expression in HPIs have tested only a small number of miRNAs ( 25 – 28 ). Of the two more comprehensive sequencing-based studies of HPI miRNAs ( 29 , 30 ), both have been limited in sample size (n ≤ 7).…”

mentioning

confidence: 99%

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.

View full text Add to dashboard Cite

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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“…Analysis of the ceRNA regulatory network associated with ETV5 indicated that ETV5 is regulated by miR-8067 in glioblastoma [ 122 ]. In human islets, the expression of ETV5 is correlated with miR-200c [ 123 ]. MiR-200c directly binds the 3′-untranslated terminal region (UTR) of ETV5 mRNA and reduces ETV5 expression, which decreased glucose-stimulated insulin secretion in type 2 diabetes [ 123 ].…”

Section: Dysregulation Of Etv5 Expressionmentioning

confidence: 99%

“…In human islets, the expression of ETV5 is correlated with miR-200c [ 123 ]. MiR-200c directly binds the 3′-untranslated terminal region (UTR) of ETV5 mRNA and reduces ETV5 expression, which decreased glucose-stimulated insulin secretion in type 2 diabetes [ 123 ]. Recently, it was demonstrated that miR-219 plays a critical role in central neuron system myelination and remyelination after injury [ 124 ].…”

Section: Dysregulation Of Etv5 Expressionmentioning

confidence: 99%

E26 transformation-specific transcription variant 5 in development and cancer: modification, regulation and function

et al. 2023

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E26 transformation-specific (ETS) transcription variant 5 (ETV5), also known as ETS-related molecule (ERM), exerts versatile functions in normal physiological processes, including branching morphogenesis, neural system development, fertility, embryonic development, immune regulation, and cell metabolism. In addition, ETV5 is repeatedly found to be overexpressed in multiple malignant tumors, where it is involved in cancer progression as an oncogenic transcription factor. Its roles in cancer metastasis, proliferation, oxidative stress response and drug resistance indicate that it is a potential prognostic biomarker, as well as a therapeutic target for cancer treatment. Post-translational modifications, gene fusion events, sophisticated cellular signaling crosstalk and non-coding RNAs contribute to the dysregulation and abnormal activities of ETV5. However, few studies to date systematically summarized the role and molecular mechanisms of ETV5 in benign diseases and in oncogenic progression. In this review, we specify the molecular structure and post-translational modifications of ETV5. In addition, its critical roles in benign and malignant diseases are summarized to draw a panorama for specialists and clinicians. The updated molecular mechanisms of ETV5 in cancer biology and tumor progression are delineated. Finally, we prospect the further direction of ETV5 research in oncology and its potential translational applications in the clinic.

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Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion

Cited by 22 publications

References 34 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

E26 transformation-specific transcription variant 5 in development and cancer: modification, regulation and function

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