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Background  Histone deacetylases (HDACs) are epigenetic factors that function to repress gene transcription by removing acetyl groups from the N-terminal of histone lysines. Histone deacetylase 4 (HDAC4), a class IIa HDAC, has previously been shown to regulate the process of endochondral ossification in mice via repression of Myocyte enhancer factor 2c (MEF2C), a transcriptional activator of  Runx2 , which in turn promotes chondrocyte maturation and production of bone by osteoblasts.    Methods & Materials  In this study, we generated two zebrafish lines with mutations in  hdac4  using CRISPR/Cas9 and analyzed mutants for skeletal phenotypes and expression of genes known to be affected by Hdac4 expression.    Results  Lines have insertions causing a frameshift in a proximal exon of  hdac4  and a premature stop codon. Mutations are predicted to result in aberrant protein sequence and a truncated protein, eliminating the Mef2c binding domain and Hdac domain. Zygotic mutants from two separate lines show a significant increase in ossification of pharyngeal ceratohyal cartilages at 7 days post fertilization (dpf) ( p  < 0.01,  p  < 0.001). At 4 dpf, mutant larvae have a significant increase of expression of  runx2a  and  runx2b  in the ceratohyal cartilage ( p  < 0.05 and  p  < 0.01, respectively). A subset of maternal-zygotic (mz) mutant and heterozygote larvae (40%) have dramatically increased ossification at 7 dpf compared to zygotic mutants, including formation of a premature anguloarticular bone and mineralization of the first and second ceratobranchial cartilages and symplectic cartilages, which normally does not occur until fish are approximately 10 or 12 dpf. Some maternal-zygotic mutants and heterozygotes show loss of pharyngeal first arch elements (25.9% and 10.2%, respectively) and neurocranium defects (30.8% and 15.2%, respectively). Analysis of RNA-seq mRNA transcript levels and  in situ  hybridizations from zygotic stages to 75–90% epiboly indicates that  hdac4  is highly expressed in early embryos, but diminishes by late epiboly, becoming expressed again in larval stages.    Discussion  Loss of function of  hdac4  in zebrafish is associated with increased expression of  runx2a  and  runx2b  targets indicating that a role for  hdac4  in zebrafish is to repress activation of ossification of cartilage. These findings are consistent with observations of precocious cartilage ossification in  Hdac4  mutant mice, demonstrating that the function of  Hdac4  in skeletal development is conserved among vertebrates. Expression of  hdac4  mRNA in embryos younger than 256–512 cells indicates that there is a maternal contribution of  hdac4  to the early embryo. The increase in ossification and profound loss of first pharyngeal arch elements and anterior neurocranium in a subset of maternal-zygotic mutant and heterozygote larvae suggests that maternal  hdac4  functions in cartilage ossification and development of cranial neural crest-derived structures.

hdac4 mediates perichondral ossification and pharyngeal skeleton development in the zebrafish