Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets

Vasumathi Kameswaran; Nuria C Bramswig; Lindsay B McKenna; Melinda Penn; Jonathan Schug; Nicholas J Hand; Ying Chen; Inchan Choi; Anastassios Vourekas; Kyoung-Jae Won; Chengyang Liu; Kumar Vivek; Ali Naji; Joshua R Friedman; Klaus H Kaestner

doi:10.1016/j.cmet.2013.11.016

Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets

Vasumathi Kameswaran, Nuria C Bramswig, Lindsay B McKenna, Melinda Penn, Jonathan Schug, Nicholas J Hand, Ying Chen, Inchan Choi, Anastassios Vourekas, Kyoung-Jae Won, Chengyang Liu, Kumar Vivek, Ali Naji, Joshua R Friedman, Klaus H Kaestner

190 Citationer (Scopus)

Abstract

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.

Originalsprog	Engelsk
Tidsskrift	Cell Metabolism
Vol/bind	19
Udgave nummer	1
Sider (fra-til)	135-45
Antal sider	11
ISSN	1550-4131
DOI	https://doi.org/10.1016/j.cmet.2013.11.016
Status	Udgivet - 7 jan. 2014
Udgivet eksternt	Ja

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10.1016/j.cmet.2013.11.016

http://www.cell.com/article/S1550413113004877/pdf

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abstract = "Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.",

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author = "Vasumathi Kameswaran and Bramswig, {Nuria C} and McKenna, {Lindsay B} and Melinda Penn and Jonathan Schug and Hand, {Nicholas J} and Ying Chen and Inchan Choi and Anastassios Vourekas and Kyoung-Jae Won and Chengyang Liu and Kumar Vivek and Ali Naji and Friedman, {Joshua R} and Kaestner, {Klaus H}",

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AU - Kameswaran, Vasumathi

AU - Bramswig, Nuria C

AU - McKenna, Lindsay B

AU - Penn, Melinda

AU - Schug, Jonathan

AU - Hand, Nicholas J

AU - Chen, Ying

AU - Choi, Inchan

AU - Vourekas, Anastassios

AU - Won, Kyoung-Jae

AU - Liu, Chengyang

AU - Vivek, Kumar

AU - Naji, Ali

AU - Friedman, Joshua R

AU - Kaestner, Klaus H

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N2 - Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.

AB - Type 2 diabetes mellitus (T2DM) is a complex disease characterized by the inability of the insulin-producing β cells in the endocrine pancreas to overcome insulin resistance in peripheral tissues. To determine if microRNAs are involved in the pathogenesis of human T2DM, we sequenced the small RNAs of human islets from diabetic and nondiabetic organ donors. We identified a cluster of microRNAs in an imprinted locus on human chromosome 14q32 that is highly and specifically expressed in human β cells and dramatically downregulated in islets from T2DM organ donors. The downregulation of this locus strongly correlates with hypermethylation of its promoter. Using HITS-CLIP for the essential RISC-component Argonaute, we identified disease-relevant targets of the chromosome 14q32 microRNAs, such as IAPP and TP53INP1, that cause increased β cell apoptosis upon overexpression in human islets. Our results support a role for microRNAs and their epigenetic control by DNA methylation in the pathogenesis of T2DM.

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KW - Gene Expression Profiling

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KW - Insulin-Secreting Cells/metabolism

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KW - Islets of Langerhans/metabolism

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KW - Membrane Proteins/genetics

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KW - Middle Aged

KW - Molecular Sequence Data

KW - Promoter Regions, Genetic

KW - RNA, Long Noncoding/genetics

KW - RNA, Messenger/genetics

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DO - 10.1016/j.cmet.2013.11.016

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JO - Cell Metabolism

JF - Cell Metabolism

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ER -

Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets

Abstract

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