2. Academic Validation
  3. The roles of SMYD4 in epigenetic regulation of cardiac development in zebrafish

The roles of SMYD4 in epigenetic regulation of cardiac development in zebrafish

  • PLoS Genet. 2018 Aug 15;14(8):e1007578. doi: 10.1371/journal.pgen.1007578.
Deyong Xiao 1,  Huijun Wang 2,  Lili Hao 1,  Xiao Guo 2,  Xiaojing Ma 2 3,  Yanyan Qian 2,  Hongbo Chen 2,  Jing Ma 2 3,  Jin Zhang 1,  Wei Sheng 2 3,  Weinian Shou 4,  Guoying Huang 2 3,  Duan Ma 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Collaborative Innovation Center of Genetics and Development, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 2 Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China.
  • 3 Pediatric Heart Center, Children's Hospital of Fudan University, Shanghai, China.
  • 4 Cardiovascular Developmental Biology Group, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States of America.
PMID: 30110327 DOI: 10.1371/journal.pgen.1007578
Abstract

SMYD4 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.

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