PMID- 37149988 OWN - NLM STAT- MEDLINE DCOM- 20230613 LR - 20230613 IS - 1090-2104 (Electronic) IS - 0006-291X (Linking) VI - 665 DP - 2023 Jul 12 TI - Hdac1-deficiency affects the cell cycle axis Cdc25-Cdk1 causing impaired G2/M phase progression and reduced cardiomyocyte proliferation in zebrafish. PG - 98-106 LID - S0006-291X(23)00553-3 [pii] LID - 10.1016/j.bbrc.2023.04.116 [doi] AB - 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. CI - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Boos, Alena AU - Boos A AD - Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany. FAU - Gahr, Bernd Martin AU - Gahr BM AD - Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany. FAU - Park, Deung-Dae AU - Park DD AD - Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany. FAU - Braun, Verena AU - Braun V AD - Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany. FAU - Buhler, Anja AU - Buhler A AD - Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany. FAU - Rottbauer, Wolfgang AU - Rottbauer W AD - Department of Internal Medicine II, Ulm University, Ulm, Germany. FAU - Just, Steffen AU - Just S AD - Molecular Cardiology, Department of Internal Medicine II, Ulm University, Ulm, Germany. Electronic address: steffen.just@uniklinik-ulm.de. LA - eng PT - Journal Article DEP - 20230429 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - EC 3.5.1.98 (Histone Deacetylase 1) RN - EC 3.5.1.98 (HDAC1 protein, zebrafish) RN - EC 3.1.3.48 (cdc25 Phosphatases) RN - EC 2.7.11.22 (CDC2 Protein Kinase) SB - IM MH - Animals MH - Mice MH - Cell Cycle/genetics MH - Cell Division MH - Cell Proliferation MH - Histone Deacetylase 1/genetics/metabolism MH - *Myocytes, Cardiac/metabolism MH - *Zebrafish/metabolism MH - cdc25 Phosphatases/metabolism MH - CDC2 Protein Kinase/metabolism OTO - NOTNLM OT - G2/M phase arrest OT - Hdac1 OT - RNA-Seq OT - Zebrafish OT - p21 COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steffen Just reports financial support was provided by German Research Foundation. Steffen Just reports financial support was provided by Federal Ministry of Education and Research. EDAT- 2023/05/08 00:41 MHDA- 2023/05/29 06:42 CRDT- 2023/05/07 18:04 PHST- 2023/03/23 00:00 [received] PHST- 2023/04/11 00:00 [revised] PHST- 2023/04/29 00:00 [accepted] PHST- 2023/05/29 06:42 [medline] PHST- 2023/05/08 00:41 [pubmed] PHST- 2023/05/07 18:04 [entrez] AID - S0006-291X(23)00553-3 [pii] AID - 10.1016/j.bbrc.2023.04.116 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2023 Jul 12;665:98-106. doi: 10.1016/j.bbrc.2023.04.116. Epub 2023 Apr 29.