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

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

(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

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
smyd4	TU	standard conditions	Prim-5	blood vessel	ISH	Fig. 1
smyd4	TU	standard conditions	Long-pec	cardiac ventricle	ISH	Fig. 1
smyd4	TU	standard conditions	Long-pec	heart	ISH	Fig. 1
smyd4	TU	standard conditions	Prim-5	heart tube	ISH	Fig. 1
smyd4	TU	standard conditions	Bud	polster	ISH	Fig. 1
smyd4	TU	standard conditions	Bud	whole organism	ISH	Fig. 1
smyd4	TU	standard conditions	75%-epiboly	whole organism	ISH	Fig. 1
smyd4	TU	standard conditions	1-cell to Protruding-mouth	whole organism	RTPCR	Fig. 1

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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