Xiao, DeyongWang, HuijunHao, LiliGuo, XiaoMa, XiaojingQian, YanyanChen, HongboMa, JingZhang, JinSheng, WeiShou, WeinianHuang, GuoyingMa, Duan2019-05-022019-05-022018-08-15Xiao, D., Wang, H., Hao, L., Guo, X., Ma, X., Qian, Y., … Ma, D. (2018). The roles of SMYD4 in epigenetic regulation of cardiac development in zebrafish. PLoS genetics, 14(8), e1007578. doi:10.1371/journal.pgen.1007578https://hdl.handle.net/1805/19068SMYD4 belongs to a family of lysine methyltransferases. We analyzed the role of smyd4 in zebrafish development by generating a smyd4 mutant zebrafish line (smyd4L544Efs*1) using the CRISPR/Cas9 technology. The maternal and zygotic smyd4L544Efs*1 mutants demonstrated severe cardiac malformations, including defects in left-right patterning and looping and hypoplastic ventricles, suggesting that smyd4 was critical for heart development. Importantly, we identified two rare SMYD4 genetic variants in a 208-patient cohort with congenital heart defects. Both biochemical and functional analyses indicated that SMYD4(G345D) was pathogenic. Our data suggested that smyd4 functions as a histone methyltransferase and, by interacting with HDAC1, also serves as a potential modulator for histone acetylation. Transcriptome and bioinformatics analyses of smyd4L544Efs*1 and wild-type developing hearts suggested that smyd4 is a key epigenetic regulator involved in regulating endoplasmic reticulum-mediated protein processing and several important metabolic pathways in developing zebrafish hearts.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesEmbryonic developmentEpigenesis -- geneticHistone Deacetylase 1Histone MethyltransferasesHistone-Lysine N-MethyltransferaseArticle