ArticleDevelopmental cell2022
Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.
Article in Developmental cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- Mechanisms underlying disease-causing variants in promoters and enhancers.Nature genetics · 2026Review
- Functional genomics analysis of developing zebrafish and human endoderm reveals highly conservedGenome research · 2026Article
- Latent plasticity of the human pancreas across development, health, and disease.bioRxiv : the preprint server for biology · 2025Article
- HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes.Cell metabolism · 2025Article
- A RareInternational journal of endocrinology and metabolism · 2025Article
- Identification of mouse and human embryonic pancreatic cells with adult ProcrFrontiers in endocrinology · 2025Article
- Neonatal diabetes mellitus around the world: Update 2024.Journal of diabetes investigation · 2024Review
- Sexually dimorphic renal expression of mouse Klotho is directed by a kidney-specific distal enhancer responsive to HNF1b.Communications biology · 2024Article
- CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant.Cell reports · 2024Article
- MODY Only Monogenic? A Narrative Review of theInternational journal of molecular sciences · 2024Review
- Transcription regulation by long non-coding RNAs: mechanisms and disease relevance.Nature reviews. Molecular cell biology · 2024Review
- A mammalian tripartite enhancer cluster controls hypothalamicProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Sexually dimorphic renal expression ofResearch square · 2024Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations.
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Registered trials
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