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Integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D-associated genes and regulatory signals [single cell]

ABSTRACT: Genome-wide association studies (GWAS) have identified over 100 signals associated with type 1 diabetes (T1D). However, it has been challenging to translate any given T1D GWAS signal into mechanistic insights, such as causal variants, their target genes, and the specific cell types involved. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in human pancreatic islets under baseline and T1D-stimulating conditions. We nominate effector cell types for all T1D GWAS signals and the regulatory elements and genes for three independent T1D signals acting through beta cells at the DLK1/MEG3, RASGRP1, and TOX loci. We validated the functional impact of these genes and regulatory regions using isogenic human embryonic stem cells (hESCs). Loss of RASGRP1 or DLK1, as well as disruption of their corresponding regulatory regions, led to increased beta cell apoptosis, and beta cells derived from isogenic hESCs carrying the T1D risk allele of rs3783355 showed elevated beta cell death. Through additional RNA-seq and ATAC-seq analyses, we identified five genes upregulated in both RASGRP1-/- and DLK1-/- beta-like cells, four of which are near T1D GWAS signals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335464 | GEO | 2026/06/16

REPOSITORIES: GEO

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.

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Integrative single-cell multi-omics profiling of human pancreatic islets identifies T1D-associated genes and regulatory signals [single cell]

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