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

Cell Metab. 2014 Jan 7;19(1):135-45. doi: 10.1016/j.cmet.2013.11.016. Epub 2013 Dec 26.


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.

MeSH terms

  • Adult
  • Base Sequence
  • Calcium-Binding Proteins
  • Chromosomes, Human, Pair 14 / genetics
  • Diabetes Mellitus, Type 2 / genetics*
  • Down-Regulation / genetics
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Profiling
  • Genomic Imprinting
  • Humans
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology*
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Middle Aged
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Young Adult


  • Calcium-Binding Proteins
  • DLK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • MEG3 non-coding RNA, human
  • Membrane Proteins
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA, Messenger