The dysregulation of the DLK1-MEg3 locus in islets from patients with type 2 diabetes is mimicked by targeted epimutation of its promoter with TALE-DNMT constructs

Vasumathi Kameswaran, Maria L. Golson, Mireia Ramos-Rodríguez, Kristy Ou, Yue J. Wang, Jia Zhang, Lorenzo Pasquali, Klaus H. Kaestner

Research output: Contribution to journalArticlepeer-review

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by the inability of the insulin-producing b-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, the DLK1-MEG3 locus, as being downregulated in islets from humans with T2DM. In this study, using targeted epigenetic modifiers, we prove that increased methylation at the promoter of Meg3 in mouse bTC6 b-cells results in decreased transcription of the maternal transcripts associated with this locus. As a result, the sensitivity of b-cells to cytokine-mediated oxidative stress was increased. Additionally, we demonstrate that an evolutionarily conserved intronic region at the MEG3 locus can function as an enhancer in bTC6 b-cells. Using circular chromosome conformation capture followed by high-throughput sequencing, we demonstrate that the promoter of MEG3 physically interacts with this novel enhancer and other putative regulatory elements in this imprinted region in human islets. Remarkably, this enhancer is bound in an allele-specific manner by the transcription factors FOXA2, PDX1, and NKX2.2. Overall, these data suggest that the intronic MEG3 enhancer plays an important role in the regulation of allele-specific expression at the imprinted DLK1-MEG3 locus in human b-cells, which in turn impacts the sensitivity of b-cells to cytokine-mediated oxidative stress.

Original languageEnglish (US)
Pages (from-to)1807-1815
Number of pages9
JournalDiabetes
Volume67
Issue number9
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Fingerprint Dive into the research topics of 'The dysregulation of the DLK1-MEg3 locus in islets from patients with type 2 diabetes is mimicked by targeted epimutation of its promoter with TALE-DNMT constructs'. Together they form a unique fingerprint.

Cite this