Imperial College London
Alternate

ProfessorJorgeFerrer

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Chair in Medicine and Genetics
 
 
 
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Contact

 

+44 (0)20 7594 0968j.ferrer

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Miguel-Escalada:2022:10.1016/j.devcel.2022.07.014,
author = {Miguel-Escalada, I and Maestro, MÁ and Balboa, D and Elek, A and Bernal, A and Bernardo, E and Grau, V and García-Hurtado, J and Sebé-Pedrós, A and Ferrer, J},
doi = {10.1016/j.devcel.2022.07.014},
journal = {Developmental Cell},
pages = {1922--1936.e9},
title = {Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.},
url = {http://dx.doi.org/10.1016/j.devcel.2022.07.014},
volume = {57},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Miguel-Escalada,I
AU  - Maestro,MÁ
AU  - Balboa,D
AU  - Elek,A
AU  - Bernal,A
AU  - Bernardo,E
AU  - Grau,V
AU  - García-Hurtado,J
AU  - Sebé-Pedrós,A
AU  - Ferrer,J
DO  - 10.1016/j.devcel.2022.07.014
EP  - 1936
PY  - 2022///
SN  - 1534-5807
SP  - 1922
TI  - Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.
T2  - Developmental Cell
UR  - http://dx.doi.org/10.1016/j.devcel.2022.07.014
UR  - https://www.ncbi.nlm.nih.gov/pubmed/35998583
UR  - https://www.sciencedirect.com/science/article/pii/S1534580722005317?via%3Dihub
UR  - http://hdl.handle.net/10044/1/99332
VL  - 57
ER  -
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