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Hu, M.* ; Cebola, I.* ; Carrat, G.* ; Jiang, S.* ; Nawaz, S.* ; Khamis, A.* ; Canouil, M.* ; Froguel, P.* ; Schulte, A.* ; Solimena, M. ; Ibberson, M.* ; Marchetti, P.* ; Cardenas-Diaz, F.L.* ; Gadue, P.J.* ; Hastoy, B.* ; Alemeida-Souza, L.* ; McMahon, H.* ; Rutter, G.A.*

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.

Cell Rep. 34:108703 (2021)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-βH1 cells impairs glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Fchsd2 ; Gwas ; Stard10 ; T2d ; Chromatin Structure ; Enhancer Cluster ; Gene Regulation ; Genetic Variant ; Insulin Secretion ; Type 2 Diabetes; Genome-wide Association; Genetic Architecture; Provides Insights; Enhancer; Ctcf; Transcription; Expression; Pathophysiology; Defines; Islets
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 34, Issue: 5, Pages: , Article Number: 108703 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502600-001
Grants EFPIA
MRC
Experimental Challenge Grant (DIVA)
Medical Research Council (MRC) Programme grants
Diabetes UK
European Union
European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking
Imperial Biomedical Research Centre
National Institute for Health Research (NIHR)
Government Department for Business, Energy, and Industrial Strategy
Global Challenges Research Fund
British Heart Foundation
Royal Society Wolfson Research Merit Award
Imperial Confidence in Concept (ICiC) grants
Wellcome Trust
DOI 10.1016/j.celrep.2021.108703
WOS ID WOS:000615235900010
Scopus ID 85100387290
PubMed ID 33535042
Erfassungsdatum 2021-04-01
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