A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes [RNA-seq]

In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic and functional studies we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations. RNA-sequencing (RNA-seq) of pancreatic progenitors (PP) differentiated from hESCs (HUES8). The following genotypes were generated with CRISPR/Cas9 gene editing and used for RNA-seq: Wildtype (WT), ONECUT1 knockouts (heterozygous and homozygous), 108 kb deletion of Patient 1 (Pat1-del; heterozygous and homozygous), heterozygous Pat1-del in heterozygous ONECUT1 deleted clones (orientation of deletions in cis or trans).