PUBLICATION

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

Authors

Xiao, D., Wang, H., Hao, L., Guo, X., Ma, X., Qian, Y., Chen, H., Ma, J., Zhang, J., Sheng, W., Shou, W., Huang, G., Ma, D.

ID

ZDB-PUB-180816-16

Date

2018

Source

PLoS Genetics 14: e1007578 (Journal)

Registered Authors

Keywords

none

MeSH Terms

Cohort Studies
Zebrafish/embryology
Zebrafish/genetics*
Histone-Lysine N-Methyltransferase/genetics
Histone-Lysine N-Methyltransferase/physiology*
Male
Histone Deacetylase 1/genetics
Histone Deacetylase 1/physiology
Histone Methyltransferases/genetics
Histone Methyltransferases/physiology*
Gene Expression Regulation, Developmental
Adolescent
Mutation, Missense
Zebrafish Proteins/genetics
Zebrafish Proteins/physiology*
Epigenesis, Genetic*
Transcriptome
Child, Preschool
Humans
Embryonic Development/drug effects
Heart Defects, Congenital/genetics
Protein Conformation
Infant
CRISPR-Cas Systems
Gene Expression Profiling
Sequence Analysis, RNA
Animals
Female
Child
Disease Models, Animal
Exome Sequencing
Heart/drug effects
Heart/embryology

(all 33)

PubMed

30110327 Full text @ PLoS Genet.

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
smyd4^zf3020/+; zf2036Tg	standard conditions	Long-pec	cardiac ventricle hypoplastic, abnormal	Fig. S2
smyd4^zf3020/+; zf2036Tg	standard conditions	Long-pec	determination of heart left/right asymmetry disrupted, abnormal	Fig. S2
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	blood accumulation ventral aorta, abnormal	Fig. 3
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	cardiac muscle cell cell population proliferation decreased occurrence, abnormal	Fig. S4
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	cardiac muscle cell cell population proliferation decreased occurrence, abnormal	Fig. 4
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	cardiac ventricle hypoplastic, abnormal	Fig. S2
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	compact layer of ventricle increased thickness, abnormal	Fig. 4
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	determination of heart left/right asymmetry disrupted, abnormal	Fig. S2
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	heart apoptotic process normal occurrence, normal	Fig. S5
smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	Long-pec	histone methyltransferase activity decreased process quality, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
zf2036Tg	Tg(myl7:EGFP)	Transgenic Insertion
zf3020		Insertion	smyd4

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
congenital heart disease			TAS
congenital heart disease	smyd4^{zf3020/zf3020}; zf2036Tg	standard conditions	IC

Sequence Targeting Reagents

Target	Reagent	Reagent Type
smyd4	CRISPR1-smyd4	CRISPR
smyd4	CRISPR2-smyd4	CRISPR
smyd4	CRISPR3-smyd4	CRISPR

Fish

Fish
smyd4^zf3020/+; zf2036Tg
smyd4^{zf3020/zf3020}; zf2036Tg
TU

Antibodies

Orthology

Gene	Orthology
smyd4

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Xiao et al., 2018 ZDB-PUB-180816-16 PMID:30110327

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

Xiao et al., 2018

ZDB-PUB-180816-16
PMID:30110327