Human-specific gene regulation in pancreatic beta-cell development (360G-Wellcome-224600_Z_21_Z)

This proposal builds on novel insights from our recent genetic discovery that a primate-specific KRAB Zinc Finger Protein (KZFP), ZNF808, is required for human pancreatic development. Our preliminary studies show that ZNF808 silences primate-specific MER11 transposons and that these need to be controlled for normal pancreas development, underscoring that this process differs between humans and rodents. This project brings together an international and interdisciplinary group of experts to uncover the role and implications of human-specific regulation in pancreatic beta-cell development. We will: 1\. Dissect the interplay between ZNF808 and other primate-specific KZFPs, MER11 elements, and transcription factors in pancreas development. This will use stem cell-derived models of beta-cell differentiation coupled with genome editing, functional genomics and computational approaches; 2\. Sequence and analyse the genome of patients with diabetes to identify novel genes essential for beta-cell development and causal mutations in regulatory elements, focusing on transcription factor binding sites within primate- specific MER11 elements; 3\. Assess the impact of disrupted human beta-cell development by examining the phenotype, post-natal growth and metabolism of patients with mutations disrupting beta-cell development and fetal insulin secretion. These investigations will provide essential new knowledge to propel scientific efforts aimed at cell-based therapies for people with diabetes.