@article{7f805be477c149aa82199391b9b3fb98,
title = "Epigenetic regulation of the DLK1-MEG3 MicroRNA cluster in human type 2 diabetic islets",
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.",
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 Won, {Kyoung Jae} and Chengyang Liu and Kumar Vivek and Ali Naji and Friedman, {Joshua R.} and Kaestner, {Klaus H.}",
note = "Funding Information: We thank Christopher Krapp and Marisa S. Bartolomei for useful comments and technical assistance with methylation analysis. We also thank Henry Hoff from the Wistar Protein Expression Facility for technical assistance with virus preparation. We are grateful to members of the Kaestner lab, Dr. Jeffrey C. Raum, and Dr. Scott A. Soleimanpour for useful discussions and critical comments on the manuscript. The program for provision of human pancreatic islets is supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant U01 DK070430 and by the Beckman Research Center/NIDDK/Integrated Islet Distribution Program grant 10028044. Human islets were also provided by the National Disease Research Interchange, with support from NIH grant U42-RR006042. We thank the University of Pennsylvania Diabetes Research Center (DRC) for the use of the Next Generation Sequencing Core (P30-DK19525). This work was supported by NIH grants R01-DK088383 and U01-DK089529 to K.H.K., and the Marilyn Fishman Grant for Diabetes Research from Endocrine Fellows Foundation to M.P. ",
year = "2014",
month = jan,
day = "7",
doi = "10.1016/j.cmet.2013.11.016",
language = "English (US)",
volume = "19",
pages = "135--145",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}
