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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)135-145
Number of pages11
JournalCell Metabolism
Volume19
Issue number1
DOIs
StatePublished - Jan 7 2014

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MicroRNAs
Epigenomics
Type 2 Diabetes Mellitus
Down-Regulation
Tissue Donors
Human Chromosomes
DNA Methylation
Islets of Langerhans
Insulin Resistance
Chromosomes
RNA
Insulin
Apoptosis

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Kameswaran, V., Bramswig, N. C., McKenna, L. B., Penn, M., Schug, J., Hand, N. J., ... Kaestner, K. H. (2014). Epigenetic regulation of the DLK1-MEG3 MicroRNA cluster in human type 2 diabetic islets. Cell Metabolism, 19(1), 135-145. https://doi.org/10.1016/j.cmet.2013.11.016

Epigenetic regulation of the DLK1-MEG3 MicroRNA cluster in human type 2 diabetic islets. / Kameswaran, Vasumathi; Bramswig, Nuria C.; McKenna, Lindsay B.; Penn, Melinda; Schug, Jonathan; Hand, Nicholas J.; Chen, Ying; Choi, Inchan; Vourekas, Anastassios; Won, Kyoung Jae; Liu, Chengyang; Vivek, Kumar; Naji, Ali; Friedman, Joshua R.; Kaestner, Klaus H.

In: Cell Metabolism, Vol. 19, No. 1, 07.01.2014, p. 135-145.

Research output: Contribution to journalArticle

Kameswaran, V, Bramswig, NC, McKenna, LB, Penn, M, Schug, J, Hand, NJ, Chen, Y, Choi, I, Vourekas, A, Won, KJ, Liu, C, Vivek, K, Naji, A, Friedman, JR & Kaestner, KH 2014, 'Epigenetic regulation of the DLK1-MEG3 MicroRNA cluster in human type 2 diabetic islets', Cell Metabolism, vol. 19, no. 1, pp. 135-145. https://doi.org/10.1016/j.cmet.2013.11.016
Kameswaran V, Bramswig NC, McKenna LB, Penn M, Schug J, Hand NJ et al. Epigenetic regulation of the DLK1-MEG3 MicroRNA cluster in human type 2 diabetic islets. Cell Metabolism. 2014 Jan 7;19(1):135-145. https://doi.org/10.1016/j.cmet.2013.11.016
Kameswaran, Vasumathi ; Bramswig, Nuria C. ; McKenna, Lindsay B. ; Penn, Melinda ; Schug, Jonathan ; Hand, Nicholas J. ; Chen, Ying ; Choi, Inchan ; Vourekas, Anastassios ; Won, Kyoung Jae ; Liu, Chengyang ; Vivek, Kumar ; Naji, Ali ; Friedman, Joshua R. ; Kaestner, Klaus H. / Epigenetic regulation of the DLK1-MEG3 MicroRNA cluster in human type 2 diabetic islets. In: Cell Metabolism. 2014 ; Vol. 19, No. 1. pp. 135-145.
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