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

• DOI: 10.2337/db17-0682
• Publication Date: 2018-07-03T13:54:47Z
• Authors: Vasumathi Kameswaran; Maria L. Golson; Mireia Ramos-Rodr...; Kristy Ou; Yue J. Wang; Jia Zhang; Lorenzo Pasquali; Klaus H. Kaestner
• Keywords: MEG3; Chromosome conformation capture; FOXA2; Forkhead Transcription Factors; Enhancer RNAs; Genomic Imprinting

Type 2 diabetes mellitus (T2DM) is characterized by the inability of insulin-producing β-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, 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 promoter Meg3 mouse βTC6 results decreased transcription maternal transcripts associated locus. As a result, sensitivity cytokine-mediated oxidative stress was increased. Additionally, demonstrate evolutionarily conserved intronic MEG3 locus can function enhancer β-cells. Using circular conformation capture followed high-throughput sequencing, physically interacts novel and other putative regulatory elements human islets. Remarkably, bound allele-specific manner factors FOXA2, PDX1, NKX2.2. Overall, these data suggest plays important role regulation expression β-cells, which turn impacts stress.