Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a regulator of insulin secretion
Year: 2021
Type: 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.
Source: Cell Reports
Institutions: Hammersmith Hospital, Imperial College London, Churchill Hospital, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Centre National de la Recherche Scientifique, Université de Lille, Institut Pasteur de Lille, Sanofi (Germany), Paul Langerhans Institute Dresden, Technische Universität Dresden, SIB Swiss Institute of Bioinformatics, University of Pisa, Children's Hospital of Philadelphia, University of Pennsylvania, University of Helsinki, HiLIFE – Elämäntieteiden Instituutti, MRC Laboratory of Molecular Biology, Nanyang Technological University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Wellcome Trust, Department for Business, Energy and Industrial Strategy, UK Government, European Federation of Pharmaceutical Industries and Associations, National Institute for Health and Care Research, British Heart Foundation, Royal Society, Diabetes UK, Academy of Medical Sciences, Imperial College London, European Commission, Innovative Medicines Initiative, Servier, Horizon 2020 Framework Programme, Medical Research Council, Horizon 2020, NIHR Imperial Biomedical Research Centre, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Investigating the role of immature beta cells in insulin release from the intact islet, G130968091, G1335979935, G1635243398, Genetic and nutritional control of pancreatic beta cell identity., G1937207371, Roles of GWA genes in controlling pancreatic beta cell function and mass., G2040450235, G2136847195, Control of glucagon secretion by AMPK and related kinases., G3277167446, G3346581055, G3555667338, G434337789, Assessing risk and progression of prediabetes and type 2 diabetes to enable disease modification - Sofia ref.: 115881, G4426574518, HNF1A in human endocrine cell development and function, G4781795914, All-optical deconstruction of the islet wiring patterns underlying insulin secretion in health and disease, G5482254092, G5485930741, Targeting etiologic molecular mechanisms to treat human diabetes, G5673545276, The impact of long non-coding RNA at the Pax6 locus on beta cell identity and function, G6133425169, Defining the molecular and physiological mechanisms of pancreatic islet dysfunction which lead to type 2 diabetes, Targeting GLP-1 receptor trafficking to improve therapies for type 2 diabetes, G6693145033, Coordination and Advancement of sub-Saharan Africa-EU Science & Technology Cooperation Network, Understanding pancreatic beta cell connectivity, Molecular mechanisms linking Sorcin to pancreatic beta cell lipotoxicity and ER Ca2+ stores., G7328074751, G7571465722, Insulin vesicle dynamics in Type 2 Diabetes, G8635620823, G8640525208, G8897119323, G9000168923
OpenAlex ID: W3128839584