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
- PubMed
- 37149988 Full text @ Biochem. Biophys. Res. Commun.
Citation
Boos, A., Gahr, B.M., Park, D.D., Braun, V., Bühler, A., Rottbauer, W., Just, S. (2023) Hdac1-deficiency affects the cell cycle axis Cdc25-Cdk1 causing impaired G2/M phase progression and reduced cardiomyocyte proliferation in zebrafish. Biochemical and Biophysical Research Communications. 665:9810698-106.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping