Functional analysis of the lncRNA MIR503HG in endothelial cell identity and endothelial-to-mesenchymal transition

Endothelial-to-mesenchymal transition (EndMT), a dynamic biological process with functional importance in cardiac development, is involved in a variety of pathological vascular remodelling scenarios.

Despite our growing understanding of the key cellular alterations required, the precise molecular determinants governing this phenotypical transition remain elusive.

With long non-coding RNAs (lncRNAs) now emerging as powerful regulators of gene expression, we sought to understand their role in EndMT. We have identified the genomic locus hosting the lncRNA MIR503HG as necessary to maintain EC identity and function.

Using small vessel remodelling in pulmonary hypertension as a paradigm, our loss- and gain-of-function approaches further demonstrated that loss of MIR503HG is a causal event in EndMT.

Here, we aim to further dissect the role of the MIR503HG locus by implementing CRISPR/Cas9 systems both in vitro and in vivo.

This strategy will assess causality in vitro using primary human cells and in vivo using a novel genetically engineered mouse model. We will also provide a first evaluation of a novel therapeutic approach by CRISPR activation of the locus.