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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.

HDAC1-mediated repression of the retinoic acid-responsive gene ripply3 promotes second heart field development