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Leprdb Mouse Model of Type 2 Diabetes: Pancreatic Islet Isolation and Live-cell 2-Photon Imaging Of Intact Islets
Published on: May 11, 2015
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Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C
Nicholas A Wachowski1,2, James A Pippin1,2, Keith Boehm1,2
1Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Diabetologia
|September 6, 2024
Summary
This study identifies 810 candidate genes influencing type 2 diabetes risk by integrating multiple sequencing datasets. Functional experiments confirmed a link between SMCO4 gene expression and insulin secretion in pancreatic cells.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Genome-wide association studies (GWAS) have identified numerous type 2 diabetes (T2D) risk loci, predominantly in non-coding regions.
- Identifying the specific genes (effector genes) regulated by these non-coding variants is challenging due to the complex cellular environments involved.
Purpose of the Study:
- To identify effector genes associated with T2D risk variants.
- To characterize chromatin and gene expression profiles in relevant cell types for T2D.
- To provide a resource for functional follow-up studies.
Main Methods:
- Generation and integration of promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq), and RNA-seq data.
- Analysis of pancreatic beta cells (EndoC-BH1), hepatocytes (HepG2), and adipocytes (SGBS).
- Variant-to-gene analysis and partitioned linkage disequilibrium score regression.
Main Results:
- Implicated 810 candidate effector genes at 370 T2D risk loci.
- Enriched T2D and fasting glucose GWAS loci in promoter-regulatory elements in pancreatic beta cells.
- Enriched fasting insulin GWAS loci in adipocytes.
- Demonstrated a significant increase in insulin secretion upon SMCO4 gene knockdown in pancreatic beta cells.
Conclusions:
- Provides a valuable resource of tissue-specific data in tractable cellular models for T2D research.
- Facilitates the study of non-coding variant effects in relevant cell types.
- Highlights SMCO4 as a potential target for further investigation in T2D.
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