PLoS Genetics (Aug 2018)

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

  • Deyong Xiao,
  • Huijun Wang,
  • Lili Hao,
  • Xiao Guo,
  • Xiaojing Ma,
  • Yanyan Qian,
  • Hongbo Chen,
  • Jing Ma,
  • Jin Zhang,
  • Wei Sheng,
  • Weinian Shou,
  • Guoying Huang,
  • Duan Ma

DOI
https://doi.org/10.1371/journal.pgen.1007578
Journal volume & issue
Vol. 14, no. 8
p. e1007578

Abstract

Read online

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.