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

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Title: Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion
Authors: Hu, M
Carrat, G
Jiang, S
Nawaz, S
Khamnis, A
Canouil, M
Froguel, P
Schulte, A
Solimena, M
Ibberson, M
Marchetti, P
Cardenas-Diaz, F
Gadue, P
Histoy, B
Alemiedia-Souza, L
McMahon, H
Rutter, G
Item Type: Journal Article
Abstract: 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.
Issue Date: 2-Feb-2021
Date of Acceptance: 8-Jan-2021
URI: http://hdl.handle.net/10044/1/86586
DOI: 10.1016/j.celrep.2021.108703
ISSN: 2211-1247
Publisher: Elsevier
Journal / Book Title: Cell Reports
Volume: 34
Issue: 5
Copyright Statement: © 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: MRC Programme Grant
Wellcome Trust
Funder's Grant Number: MR/R022259/1
Keywords: FCHSD2
chromatin structure
enhancer cluster
gene regulation
genetic variant
insulin secretion
type 2 diabetes
0601 Biochemistry and Cell Biology
1116 Medical Physiology
Publication Status: Published
Article Number: ARTN 108703
Online Publication Date: 2021-02-02
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine

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