Associated organisationsUniversity of Cambridge · University of Exeter · University of Exeter Medical School · University of HelsinkiEurope PMC affiliations are not treated as award recipients or mapped locations.
Funding£3.5M
PeriodApr 2022 — Mar 2027
In plain English
AI plain-English summary
A single gene, ZNF808, that only exists in primates must silence ancient viral DNA for a human pancreas to form properly. This matters because most diabetes research relies on mice, but their pancreas develops differently from ours. The discovery that a primate-specific gene controls human beta-cell development reveals a fundamental gap in knowledge—what works in rodents may not translate to humans. The researchers will use stem cell models and genome editing to map how ZNF808 and other primate-specific genes orchestrate this process, and they will sequence DNA from diabetes patients to find mutations in these uniquely human regulatory elements. If successful, this fundamental science will provide the essential blueprint for building functional human beta cells in the lab. That knowledge is a prerequisite for cell-based therapies that could one day restore insulin production in people with diabetes. There is no immediate practical application—this is discovery-driven research into why human pancreas development differs from that of other animals. But without understanding these species-specific mechanisms, efforts to grow replacement cells for patients will remain guesswork.
View original technical description
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.
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