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Modelling enhancer mutations causing pancreas agenesis showed that this enhancer has a lead function that renders it vulnerable to loss of function
It also shed light on key gene regulatory steps of early pancreatic endorine differentiation
cell.comπ§΅
Modelling enhancer mutations causing pancreas agenesis showed that this enhancer has a lead function that renders it vulnerable to loss of function
It also shed light on key gene regulatory steps of early pancreatic endorine differentiation
cell.comπ§΅
Loss of function mutations in a PTF1A enhancer, typically point mutations, were previously shown to cause pancreas agenesis (past collab with Hattersley, Weedon, Ellard)
So far there are hardly any firmly established human Mendelian phenotypes caused by LoF of a single enhancer (as opposed SVs that disrupt many enhancers or alter TADs, or GoF variants)
Enhancers are quite robust to LoF due to redundancy. Why is LoF of this enhancer pathogenic?
Enhancers are quite robust to LoF due to redundancy. Why is LoF of this enhancer pathogenic?
Our work now shows that this enhancer acts as a master switch that turns on other PTF1A domain enhancers in the first multipotent progenitors of the developing pancreas. This lead enhancer role explains why there is no redundancy
Interestingly, this enhancer did not have unique βsuper-enhancerβ features amongst enhancers in the same domain, it was a functional (and genetic) property
An unknown number of enhancers in the human genome are likely to have this lead function, and can harbor LoF mutations
An unknown number of enhancers in the human genome are likely to have this lead function, and can harbor LoF mutations
An enhancer KO is different from disruption of a gene: PTF1A was selectively silenced in early progenitors. Since this did not completely block pancreas development, it revealed that transient PTF1A expression programs early steps of endocrine differentiation
PTF1A specifies a pro-endocrine chromatin state in the subsequent progenitor stage, which in turn enables activation of Ngn3+ endocrine progenitors
Stellar work from Irene Miguel Escalada (co-corresponding author), Miguel A. Maestro, Diego Balboa, Anamaria Elek, Arnau Sebe
Open access thanks to @wellcometrust
Open access thanks to @wellcometrust
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