Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C.

Chromatin conformation Epigenetics Insulin secretion SMCO4 Type 2 diabetes Variant to gene mapping

Journal

Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777

Informations de publication

Date de publication:
06 Sep 2024
Historique:
received: 28 03 2024
accepted: 04 07 2024
medline: 6 9 2024
pubmed: 6 9 2024
entrez: 6 9 2024
Statut: aheadofprint

Résumé

Genome-wide association studies (GWAS) have identified hundreds of type 2 diabetes loci, with the vast majority of signals located in non-coding regions; as a consequence, it remains largely unclear which 'effector' genes these variants influence. Determining these effector genes has been hampered by the relatively challenging cellular settings in which they are hypothesised to confer their effects. To implicate such effector genes, we elected to generate and integrate high-resolution promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq datasets to characterise chromatin and expression profiles in multiple cell lines relevant to type 2 diabetes for subsequent functional follow-up analyses: EndoC-BH1 (pancreatic beta cell), HepG2 (hepatocyte) and Simpson-Golabi-Behmel syndrome (SGBS; adipocyte). The subsequent variant-to-gene analysis implicated 810 candidate effector genes at 370 type 2 diabetes risk loci. Using partitioned linkage disequilibrium score regression, we observed enrichment for type 2 diabetes and fasting glucose GWAS loci in promoter-connected putative cis-regulatory elements in EndoC-BH1 cells as well as fasting insulin GWAS loci in SGBS cells. Moreover, as a proof of principle, when we knocked down expression of the SMCO4 gene in EndoC-BH1 cells, we observed a statistically significant increase in insulin secretion. These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings. Raw and processed next-generation sequencing data for EndoC-BH1, HepG2, SGBS_undiff and SGBS_diff cells are deposited in GEO under the Superseries accession GSE262484. Promoter-focused Capture-C data are deposited under accession GSE262496. Hi-C data are deposited under accession GSE262481. Bulk ATAC-seq data are deposited under accession GSE262479. Bulk RNA-seq data are deposited under accession GSE262480.

Identifiants

DOI: 10.1007/s00125-024-06261-x PMID: 39240351
pubmed: 39240351
doi: 10.1007/s00125-024-06261-x
pii: 10.1007/s00125-024-06261-x
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Children's Hospital of Philadephia
ID : Daniel B. Burke Endowed Chair for Diabetes Researc
Organisme : Eunice Kennedy Shriver National Institute of Child Health and Human Development
ID : R01HD056465
Organisme : NIDDK NIH HHS
ID : UM1 DK126194
Pays : United States

Informations de copyright

© 2024. The Author(s).

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Auteurs

Nicholas A Wachowski (NA)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

James A Pippin (JA)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Keith Boehm (K)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Sumei Lu (S)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Michelle E Leonard (ME)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Elisabetta Manduchi (E)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Ursula W Parlin (UW)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Martin Wabitsch (M)

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

Alessandra Chesi (A)

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Andrew D Wells (AD)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Struan F A Grant (SFA)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. grants@chop.edu.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. grants@chop.edu.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. grants@chop.edu.
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. grants@chop.edu.
Division of Diabetes and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. grants@chop.edu.

Matthew C Pahl (MC)

Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Classifications MeSH