Cardiovascular progenitors originate in the lateral plate mesoderm (LPM) and express overlapping sets of genes, among which is nkx2.5 which encodes a transcription factor responsible for driving cardiac fate from mesodermal progenitor. Interestingly, Nkx2.5 have also been shown to play a role in specifying the blood and vascular lineage and a subpopulation of nkx2.5-expressing cells in the LPM were found to give rise to pharyngeal arch endothelial cells. Our previous study (Pawlak et al., Genome Res. 2019) also suggests the same, in which we observed that nkx2.5-expressing cells express genes implicated in the development of, not only heart, but also haematopoiesis and vasculogenesis. This is also accompanied by the enrichment of motifs for GATA, Fli, ETS, ERG, and ETV family of TFs in open chromatin regions associated with these genes, suggesting that they are regulated at both genetic and epigenetic levels. An attractive hypothesis that arises is that a group of cells exist within the pool of nkx2.5-expressing progenitors which possess alternative potential to become cardiac or blood/vascular lineage. In order to dissect into the molecular mechanism behind this duality of function, we aim to pinpoint at which stage the segregation between cardiac and hemoangiogenic fates start to become segregated, the pathway and intermediate states these progenitors go through during lineage specification, and finally to determine the epigenetic contribution to this process. The project employs single cell transcriptomics and epigenomics analysis coupled with computational modelling of cell lineage trajectory to elucidate the mechanism of Nkx2.5-driven lineage specification of cardiac and hemoangiogenic fates.
This project is supported by the OPUS grant from the National Science Center 2019/35/B/NZ2/02548.