Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.
Détails
Télécharger: Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.pdf (4316.76 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_2303B8273031
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion.
Périodique
Cell reports
ISSN
2211-1247 (Electronic)
Statut éditorial
Publié
Date de publication
02/02/2021
Peer-reviewed
Oui
Volume
34
Numéro
5
Pages
108703
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Carrier Proteins/metabolism, Chromatin/metabolism, Humans, Insulin-Secreting Cells/metabolism, Membrane Proteins/metabolism, Phosphoproteins/metabolism, FCHSD2, GWAS, STARD10, T2D, chromatin structure, enhancer cluster, gene regulation, genetic variant, insulin secretion, type 2 diabetes
Pubmed
Web of science
Open Access
Oui
Création de la notice
08/02/2021 11:48
Dernière modification de la notice
18/06/2024 6:12