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Open Access 06-09-2024 | Type 2 Diabetes | Article

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

Authors: Nicholas A. Wachowski, James A. Pippin, Keith Boehm, Sumei Lu, Michelle E. Leonard, Elisabetta Manduchi, Ursula W. Parlin, Martin Wabitsch, Alessandra Chesi, Andrew D. Wells, Struan F. A. Grant, Matthew C. Pahl

Published in: Diabetologia

Abstract

Aims/hypothesis

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.

Methods

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).

Results

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.

Conclusions/interpretation

These results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings.

Data availability

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.

Graphical Abstract

Available only for authorised users

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Title: Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C
Authors: Nicholas A. Wachowski
James A. Pippin
Keith Boehm
Sumei Lu
Michelle E. Leonard
Elisabetta Manduchi
Ursula W. Parlin
Martin Wabitsch
Alessandra Chesi
Andrew D. Wells
Struan F. A. Grant
Matthew C. Pahl
Publication date: 06-09-2024
Publisher: Springer Berlin Heidelberg
Keywords: Type 2 Diabetes
Insulins
Insulins
Epigenetics
Published in: Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-024-06261-x

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

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Data availability

Graphical Abstract

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Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Data availability

Graphical Abstract

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2024 ESC Congress

Noise pollution dangerous for heart health

Post-TAVI follow up: deploying virtual assistants

Antihypertensives: more effective at morning or night?

Low Lp(a) levels unlikely to increase the risk of diabetes

» View more highlights on the 2024 ESC Congress hub page

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