PUBLICATION

Histone demethylases Kdm6ba and Kdm6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation

Authors

Akerberg, A.A., Henner, A., Stewart, S., Stankunas, K.

ID

ZDB-PUB-170405-6

Date

2017

Source

Developmental Biology 426(1): 84-96 (Journal)

Registered Authors

Akerberg, Alex, Stankunas, Kryn, Stewart, Scott

Keywords

H3K27me3, Kdm6b, cardiogenesis, histone demethylase, trabeculation, ventricle

MeSH Terms

Cell Differentiation/genetics
Zebrafish
Gene Expression Regulation, Developmental
Animals
Jumonji Domain-Containing Histone Demethylases/genetics*
Jumonji Domain-Containing Histone Demethylases/metabolism
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism
Animals, Genetically Modified
Cell Proliferation
Gene Knockout Techniques
Organogenesis/genetics*
Organogenesis/physiology
Methylation
Histone Demethylases/genetics*
Histone Demethylases/metabolism
Heart Ventricles/growth & development*
Histones/metabolism
Myocytes, Cardiac/cytology
Myocytes, Cardiac/metabolism*

(all 20)

PubMed

28372944 Full text @ Dev. Biol.

Abstract

Trimethylation of lysine 27 on histone 3 (H3K27me3) by the Polycomb repressive complex 2 (PRC2) contributes to localized and inherited transcriptional repression. Kdm6b (Jmjd3) is a H3K27me3 demethylase that can relieve repression-associated H3K27me3 marks, thereby supporting activation of previously silenced genes. Kdm6b is proposed to contribute to early developmental cell fate specification, cardiovascular differentiation, and/or later steps of organogenesis, including endochondral bone formation and lung development. We pursued loss-of-function studies in zebrafish to define the conserved developmental roles of Kdm6b. kdm6ba and kdm6bb homozygous deficient zebrafish are each viable and fertile. However, loss of both kdm6ba and kdm6bb shows Kdm6b proteins share redundant and pleiotropic roles in organogenesis without impacting initial cell fate specification. In the developing heart, co-expressed Kdm6b proteins promote cardiomyocyte proliferation coupled with the initial stages of cardiac trabeculation. While newly formed trabecular cardiomyocytes display a striking transient decrease in bulk cellular H3K27me3 levels, this demethylation is independent of collective Kdm6b. Our results indicate a restricted and likely locus-specific role for Kdm6b demethylases during heart ventricle maturation rather than initial cardiogenesis.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
EGFP	kdm6ba^b1308/b1308; kdm6bb^b1307/b1307; s843Tg	standard conditions	Day 5	endocardium	IHC	Fig. 5
EGFP	kdm6ba^b1308/+; kdm6bb^b1307/b1307; s843Tg	standard conditions	Day 5	endocardium	IHC	Fig. 5
kdm6a	kdm6ba^b1308/b1308	standard conditions	Prim-15	whole organism	RTPCR	Fig. 2
kdm6a	kdm6bb^b1307/b1307	standard conditions	Prim-15	whole organism	RTPCR	Fig. 2
kdm6a	WT	standard conditions	Prim-15	whole organism	RTPCR	Fig. 2
kdm6al	kdm6ba^b1308/b1308	standard conditions	Prim-15	whole organism	RTPCR	Fig. 2
kdm6al	kdm6bb^b1307/b1307	standard conditions	Prim-15	whole organism	RTPCR	Fig. 2
kdm6al	WT	standard conditions	Prim-15	whole organism	RTPCR	Fig. 2
kdm6ba	AB	standard conditions	Prim-5	brain	ISH	Fig. 1
kdm6ba	AB	standard conditions	Long-pec	heart	ISH	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
kdm6ba^b1308/+; kdm6bb^b1307/b1307	standard conditions	Day 5	whole organism morphology, normal	Fig. 3
kdm6ba^b1308/+; kdm6bb^b1307/b1307	standard conditions	Day 5	whole organism viable, normal	Fig. 3
kdm6ba^b1308/+; kdm6bb^b1307/b1307; s843Tg	standard conditions	Day 5	endocardium morphology, normal	Fig. 5
kdm6ba^b1308/b1308	standard conditions	Prim-5	whole organism morphology, normal	Fig. 2
kdm6ba^b1308/b1308	standard conditions	Prim-15	whole organism kdm6ba expression decreased amount, abnormal	Fig. 2
kdm6ba^b1308/b1308	standard conditions	Long-pec	whole organism morphology, normal	Fig. 2
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307	standard conditions	Day 5	basihyal cartilage decreased length, abnormal	Fig. 3
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307	standard conditions	Day 5	blood circulation process quality, normal	Fig. Movie S1
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307	standard conditions	Day 5	bulbus arteriosus morphology, normal	Fig. 4
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307	standard conditions	Day 5	cardiac ventricle decreased size, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
b1307		Small Deletion	kdm6bb
b1308		Small Deletion	kdm6ba
hsc4Tg	Tg(-0.8myl7:NLS-DsRedx)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
kdm6ba	CRISPR1-kdm6ba	CRISPR
kdm6bb	CRISPR4-kdm6bb	CRISPR

Fish

Fish
AB
kdm6ba^b1308/b1308
kdm6ba^b1308/b1308
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307; hsc4Tg
kdm6ba^b1308/b1308; kdm6bb^b1307/b1307; s843Tg
kdm6ba^b1308/b1308; kdm6bb^b1307/+
kdm6ba^b1308/+; kdm6bb^b1307/b1307
kdm6ba^b1308/+; kdm6bb^b1307/b1307; s843Tg
kdm6bb^b1307/b1307

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRedx	EFG	DsRedx
EGFP	EFG	EGFP

Mapping

Akerberg et al., 2017 ZDB-PUB-170405-6 PMID:28372944

Histone demethylases Kdm6ba and Kdm6bb redundantly promote cardiomyocyte proliferation during zebrafish heart ventricle maturation

Akerberg et al., 2017

ZDB-PUB-170405-6
PMID:28372944