PUBLICATION
Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development
- Authors
- Geusz, R.J., Wang, A., Chiou, J., Lancman, J.J., Wetton, N., Kefalopoulou, S., Wang, J., Qui, Y., Yan, J., Aylward, A., Ren, B., Dong, P.D.S., Gaulton, K.J., Sander, M.
- ID
- ZDB-PUB-210207-6
- Date
- 2021
- Source
- eLIFE 10: (Journal)
- Registered Authors
- Dong, P. Duc, Lancman, Joseph
- Keywords
- GWAS, Type 2 diabetes, Zebrafish, chromatin, developmental biology, genetics, genomics, hESC, human, pancreas, zebrafish
- MeSH Terms
-
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Humans
- Epigenome*
- Intracellular Signaling Peptides and Proteins/genetics*
- PubMed
- 33544077 Full text @ Elife
Abstract
Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.
Genes / Markers
Figure Gallery (8 images)
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping