Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.

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. [Display omitted] • The pancreas agenesis enhancer (EnhP) activates PTF1A in early pancreatic progenitors • EnhP also activates other progenitor PTF1A enhancers • This master key function explains why EnhP is vulnerable to loss-of-function mutations • Transient PTF1A expression in progenitors controls pancreas growth and endocrinogenesis Miguel-Escalada et al. show that pancreas agenesis mutations disrupt a lead enhancer that activates other PTF1A enhancers in early progenitors of the embryonic pancreas. This enables transient PTF1A expression in progenitors, which controls pancreas growth and creates epigenetic competence for subsequent endocrine differentiation. [ABSTRACT FROM AUTHOR]