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ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes
Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Gothenburg, Sweden.
Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7785Article in journal (Refereed) Published
Abstract [en]

Impaired insulin secretion from pancreatic islets is a hallmark of type 2 diabetes (T2D). Altered chromatin structure may contribute to the disease. We therefore studied the impact of T2D on open chromatin in human pancreatic islets. We used assay for transposase-accessible chromatin using sequencing (ATAC-seq) to profile open chromatin in islets from T2D and non-diabetic donors. We identified 57,105 and 53,284 ATAC-seq peaks representing open chromatin regions in islets of nondiabetic and diabetic donors, respectively. The majority of ATAC-seq peaks mapped near transcription start sites. Additionally, peaks were enriched in enhancer regions and in regions where islet-specific transcription factors (TFs), e.g. FOXA2, MAFB, NKX2.2, NKX6.1 and PDX1, bind. Islet ATAC-seq peaks overlap with 13 SNPs associated with T2D (e.g. rs7903146, rs2237897, rs757209, rs11708067 and rs878521 near TCF7L2, KCNQ1, HNF1B, ADCY5 and GCK, respectively) and with additional 67 SNPs in LD with known T2D SNPs (e.g. SNPs annotated to GIPR, KCNJ11, GLIS3, IGF2BP2, FTO and PPARG). There was enrichment of open chromatin regions near highly expressed genes in human islets. Moreover, 1,078 open chromatin peaks, annotated to 898 genes, differed in prevalence between diabetic and non-diabetic islet donors. Some of these peaks are annotated to candidate genes for T2D and islet dysfunction (e.g. HHEX, HMGA2, GLIS3, MTNR1B and PARK2) and some overlap with SNPs associated with T2D (e.g. rs3821943 near WFS1 and rs508419 near ANK1). Enhancer regions and motifs specific to key TFs including BACH2, FOXO1, FOXA2, NEUROD1, MAFA and PDX1 were enriched in differential islet ATAC-seq peaks of T2D versus non-diabetic donors. Our study provides new understanding into how T2D alters the chromatin landscape, and thereby accessibility for TFs and gene expression, in human pancreatic islets.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 9, article id 7785
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-385973DOI: 10.1038/s41598-019-44076-8ISI: 000468770600050PubMedID: 31123324OAI: oai:DiVA.org:uu-385973DiVA, id: diva2:1327507
Funder
Swedish Research CouncilEU, European Research Council, 725840Swedish Foundation for Strategic Research , IRC15-0067Knut and Alice Wallenberg FoundationAvailable from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved

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