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

被引：20

作者：

Xiao, Deyong ^{[1
]}

Wang, Huijun ^{[2
]}

Hao, Lili ^{[1
]}

Guo, Xiao ^{[2
]}

Ma, Xiaojing ^{[2
,3
]}

Qian, Yanyan ^{[2
]}

Chen, Hongbo ^{[2
]}

Ma, Jing ^{[2
,3
]}

Zhang, Jin ^{[1
]}

Sheng, Wei ^{[2
,3
]}

Shou, Weinian ^{[4
]}

Huang, Guoying ^{[2
,3
]}

Ma, Duan ^{[1
,2
]}

机构：

[1] Fudan Univ, Key Lab Metab & Mol Med, Collaborat Innovat Ctr Genet & Dev, Minist Educ,Inst Biomed Sci,Sch Basic Med Sci,Dep, Shanghai, Peoples R China

[2] Fudan Univ, Childrens Hosp, Shanghai Key Lab Birth Defect, Shanghai, Peoples R China

[3] Fudan Univ, Childrens Hosp, Pediat Heart Ctr, Shanghai, Peoples R China

[4] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Cardiovasc Dev Biol Grp, Indianapolis, IN 46202 USA

来源：

PLOS GENETICS | 2018年 / 14卷 / 08期

基金：

中国国家自然科学基金;

关键词：

CONGENITAL HEART-DISEASE; HISTONE METHYLTRANSFERASE; MYND DOMAIN; METHYLATION; SET; HEMATOPOIESIS; MORPHOGENESIS; ORGANIZATION; MUTATIONS; DEFECTS;

D O I：

10.1371/journal.pgen.1007578

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

SMYD4 belongs to a family of lysine methyltransferases. We analyzed the role of smyd4 in zebrafish development by generating a smyd4 mutant zebrafish line (smyd4(L544)Efs*(1)) using the CRISPR/Cas9 technology. The maternal and zygotic smyd4(L544Efs)*(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 smyd4(L544Efs)*(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.

引用

页数：24

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