PUBLICATION

Hdac1-deficiency affects the cell cycle axis Cdc25-Cdk1 causing impaired G2/M phase progression and reduced cardiomyocyte proliferation in zebrafish

Authors

Boos, A., Gahr, B.M., Park, D.D., Braun, V., Bühler, A., Rottbauer, W., Just, S.

ID

ZDB-PUB-230508-37

Date

2023

Source

Biochemical and Biophysical Research Communications 665: 9810698-106 (Journal)

Registered Authors

Boos, Alena, Gahr, Bernd, Just, Steffen, Park, Deung-Dae, Rottbauer, Wolfgang

Keywords

G2/M phase arrest, Hdac1, RNA-Seq, Zebrafish, p21

MeSH Terms

Animals
Cell Cycle/genetics
Cell Division
Cell Proliferation
Histone Deacetylase 1/genetics
Histone Deacetylase 1/metabolism
Mice
Myocytes, Cardiac*/metabolism
Zebrafish*/metabolism

(all 9)

PubMed

37149988 Full text @ Biochem. Biophys. Res. Commun.

Abstract

Zebrafish have the ability to fully regenerate their hearts after injury since cardiomyocytes subsequently dedifferentiate, re-enter cell cycle, and proliferate to replace damaged myocardial tissue. Recent research identified the reactivation of dormant developmental pathways during cardiac regeneration in adult zebrafish, suggesting pro-proliferative pathways important for developmental heart growth to be also critical for regenerative heart growth after injury. Histone deacetylase 1 (Hdac1) was recently shown to control both, embryonic as well as adult regenerative cardiomyocyte proliferation in the zebrafish model. Nevertheless, regulatory pathways controlled by Hdac1 are not defined yet. By analyzing RNA-seq-derived transcriptional profiles of the Hdac1-deficient zebrafish mutant baldrian, we here identified DNA damage response (DDR) pathways activated in baldrian mutant embryos. Surprisingly, although the DDR signaling pathway was transcriptionally activated, we found the complete loss of protein expression of the known DDR effector and cell cycle inhibitor p21. Consequently, we observed an upregulation of the p21-downstream target Cdk2, implying elevated G1/S phase transition in Hdac1-deficient zebrafish hearts. Remarkably, Cdk1, another p21-but also Cdc25-downstream target was downregulated. Here, we found the significant downregulation of Cdc25 protein expression, explaining reduced Cdk1 levels and suggesting impaired G2/M phase progression in Hdac1-deficient zebrafish embryos. To finally prove defective cell cycle progression due to Hdac1 loss, we conducted Cytometer-based cell cycle analyses in HDAC1-deficient murine HL-1 cardiomyocytes and indeed found impaired G2/M phase transition resulting in defective cardiomyocyte proliferation. In conclusion, our results suggest a critical role of Hdac1 in maintaining both, regular G1/S and G2/M phase transition in cardiomyocytes by controlling the expression of essential cell cycle regulators such as p21 and Cdc25.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism atm expression increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism atr expression increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism atrip expression increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism chek1 expression increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism chek2 expression increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism tp53 expression increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism Ab3-cdkn1a labeling decreased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism Ab5-chek2 labeling increased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism Ab6-chek1 labeling decreased amount, abnormal	Fig. 3
hdac1^{ulm107/ulm107}	standard conditions	Protruding-mouth	whole organism ab7-h2afx labeling increased amount, abnormal	Fig. 2

1 - 10 of 13

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
f2Tg	Tg(-5.1myl7:DsRed2-NLS)	Transgenic Insertion
ulm106Tg	Tg(myl7:NLS-mCherry)	Transgenic Insertion
ulm107		Point Mutation	hdac1

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed2	EFG	DsRed2
mCherry	EFG	mCherry

Mapping

Boos et al., 2023 ZDB-PUB-230508-37 PMID:37149988

Hdac1-deficiency affects the cell cycle axis Cdc25-Cdk1 causing impaired G2/M phase progression and reduced cardiomyocyte proliferation in zebrafish

Boos et al., 2023

ZDB-PUB-230508-37
PMID:37149988