Hox -Dependent Coordination of Cardiac Cell Patterning and Differentiation

During early cardiogenesis, progressive addition of distinct cardiac progenitor cells originating from the second heart field (SHF) contributes to elongation of the forming heart. Whereas the subdivision of the SHF into an anterior and posterior domain is essential for morphogenesis of the definitive heart, the transcriptional programs and upstream regulatory events operating in the different progenitor cell populations remain unclear. Here, we characterize the molecular signature and regulation of anterior and posterior sub-populations of SHF cells. We profiled the transcriptome and chromatin accessibility of purified sub-populations at genome-wide levels and demonstrated that the transcriptional regulator Hoxb1 controls the differentiation of the posterior SHF progenitors during heart morphogenesis. Spatial mis-expression of Hoxb1 in anterior SHF progenitors that normally contribute to right ventricular cardiomyocytes results in hypoplastic right ventricle, revealing how deregulation of a specific sub-population of the SHF can result in congenital heart defects. Expanded activation of Hoxb1 perturbs the anterior transcriptional program and induces increased progenitor cell death in anterior SHF progenitors. Moreover, activation of Hoxb1 in embryonic stem cells arrests cardiac differentiation, whereas Hoxb1-deficient embryos display premature differentiation of cardiac progenitor cells. Our results show that Hoxb1 coordinates a cascade of gene-regulatory events in the SHF essential for proper heart development and provide new insights into how deregulation of SHF sub-population identities can induce congenital heart defects.