ArticleCell reports2024
CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant.
Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed.
- CRISPR Technologies in Type 2 Diabetes: From Mechanistic Insights to Therapeutic Discovery.International journal of molecular sciences · 2026Review
- A dish-to-biobank framework links β-cell nutrient-stress programs to genetic and dietary risk for Type 2 Diabetes.bioRxiv : the preprint server for biology · 2026Article
- Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.Nature metabolism · 2026Article
- A robust cis-regulatory network ensures Otx2 expression during retinal development.Development (Cambridge, England) · 2026Article
- FourC: identifying significant and differential contacts in 1D chromatin conformation data.bioRxiv : the preprint server for biology · 2026Article
- The role of the beta cell in type 2 diabetes: new findings from the last 5 years.Diabetologia · 2025Review
- Discovery of NANOG enhancers and their essential roles in self-renewal and differentiation in human embryonic stem cells.Stem cell reports · 2025Article
- ChromBPNet: bias factorized, base-resolution deep learning models of chromatin accessibility reveal cis-regulatory sequence syntax, transcription factor footprints and regulatory variants.bioRxiv : the preprint server for biology · 2025Article
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Abstract
Functional enhancer annotation is critical for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants. However, unbiased enhancer discovery in disease-relevant contexts remains challenging. To identify enhancers pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers identified, we focused on an enhancer we named ONECUT1e-664kb, ∼664 kb from the ONECUT1 promoter. Previous studies have linked ONECUT1 coding mutations to pancreatic hypoplasia and neonatal diabetes. We found that homozygous deletion of ONECUT1e-664kb in hPSCs leads to a near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. ONECUT1e-664kb contains a type 2 diabetes-associated variant (rs528350911) disrupting a GATA motif. Introducing the risk variant into hPSCs reduced binding of key pancreatic transcription factors (GATA4, GATA6, and FOXA2), supporting its causal role in diabetes. This work highlights the utility of unbiased enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.
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