Abstract
Coordinated transcriptional and epigenetic mechanisms that direct development of the later differentiating second heart field (SHF) progenitors remain largely unknown. Here, we show that a novel zebrafish histone deacetylase 1 (hdac1) mutant allele cardiac really gone (crg) has a deficit of ventricular cardiomyocytes (VCs) and smooth muscle within the outflow tract (OFT) due to both cell and non-cell autonomous loss in SHF progenitor proliferation. Cyp26-deficient embryos, which have increased retinoic acid (RA) levels, have similar defects in SHF-derived OFT development. We found that nkx2.5+ progenitors from Hdac1 and Cyp26-deficient embryos have ectopic expression of ripply3, a transcriptional co-repressor of T-box transcription factors that is normally restricted to the posterior pharyngeal endoderm. Furthermore, the ripply3 expression domain is expanded anteriorly into the posterior nkx2.5+ progenitor domain in crg mutants. Importantly, excess ripply3 is sufficient to repress VC development, while genetic depletion of Ripply3 and Tbx1 in crg mutants can partially restore VC number. We find that the epigenetic signature at RA response elements (RAREs) that can associate with Hdac1 and RA receptors (RARs) becomes indicative of transcriptional activation in crg mutants. Our study highlights that transcriptional repression via the epigenetic regulator Hdac1 facilitates OFT development through directly preventing expression of the RA-responsive gene ripply3 within SHF progenitors.
Highlights
The ultimate size of all vertebrate hearts is determined through a continuous contribution of differentiating cardiac progenitors, which are often described as the first and second heart field
We find that loss of Hdac1 in zebrafish embryos leads to increased expression of genes that are induced by excess retinoic acid, a teratogen that induces similar outflow tract defects
By in situ hybridization (ISH), we found that in crg mutants neither specification of cardiac progenitors was affected at the 8 somite (s) stage nor was early differentiation of CMs affected at the 20s stage (S1 Fig), suggesting early cardiac specification and first heart field (FHF) development are not dramatically affected
Summary
The ultimate size of all vertebrate hearts is determined through a continuous contribution of differentiating cardiac progenitors, which are often described as the first and second heart field. Later-differentiating cardiac progenitors from the second heart field (SHF), which lie in the adjacent dorsal and medial pharyngeal mesoderm, contribute to the growth of the heart through adding CMs, as well as smooth muscle and endothelial cells, to the poles [1,2,3,4,5,6,7,8,9]. In the 4-chambered heart of birds and mammals, the later differentiating cells of the SHF predominantly contribute to both of the atria, the right ventricle, and smooth muscle and endothelial cells of the outflow tract (OFT) [10]. We have gained insight into the roles of these molecular players in guiding SHF development, epigenetic mechanisms that influence their transcriptional inputs during SHF development remain poorly understood
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