Abstract
Perturbation of addition of second heart field (SHF) cardiac progenitor cells to the poles of the heart tube results in congenital heart defects (CHD). The transcriptional programs and upstream regulatory events operating in different subpopulations of the SHF remain unclear. Here, we profile the transcriptome and chromatin accessibility of anterior and posterior SHF sub-populations at genome-wide levels and demonstrate that Hoxb1 negatively regulates differentiation in the posterior SHF. Spatial mis-expression of Hoxb1 in the anterior SHF results in hypoplastic right ventricle. Activation of Hoxb1 in embryonic stem cells arrests cardiac differentiation, whereas Hoxb1-deficient mouse embryos display premature cardiac differentiation. Moreover, ectopic differentiation in the posterior SHF of embryos lacking both Hoxb1 and its paralog Hoxa1 results in atrioventricular septal defects. Our results show that Hoxb1 plays a key role in patterning cardiac progenitor cells that contribute to both cardiac poles and provide new insights into the pathogenesis of CHD.
Highlights
Heart morphogenesis and patterning require precise temporal differentiation of distinct cardiac progenitor populations that arise from two early sources of mesoderm progenitors, the first heart field (FHF) and the second heart field (SHF) (Buckingham et al, 2005)
We identified 249 genes upregulated, and 292 genes downregulated in Hoxb1-/- embryos. (M) Gene ontology (GO) analysis of genes deregulated in Hoxb1-/- embryos with ranked by -log10 (p-value). (N) Chord plot showing a selection of genes upregulated in dissected pharyngeal mesoderm of Hoxb1-/- embryos present in the represented enriched GO terms
We characterize the transcriptional profile of subpopulations of SHF progenitor cells contributing to the forming heart and identify central roles of Hoxb1 in the posterior SHF
Summary
Heart morphogenesis and patterning require precise temporal differentiation of distinct cardiac progenitor populations that arise from two early sources of mesoderm progenitors, the first heart field (FHF) and the second heart field (SHF) (Buckingham et al, 2005). The SHF is a progenitor population originating in pharyngeal mesoderm that contributes to heart tube elongation through the progressive addition of cells from the dorsal pericardial wall to both poles of the forming heart. Cardiac progenitors in the aSHF contribute to the right ventricular and outflow tract myocardium (Buckingham et al, 2005), whereas pSHF cells participate to the formation of the atrial and Stefanovic et al eLife 2020;9:e55124.
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