Class II Histone Deacetylases Act As Signal-responsive Repressors of Cardiac Hypertrophy

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2002 Aug 31

PMID 12202037

Citations 451

Authors

Chun Li Zhang

Timothy A McKinsey

Shurong Chang

Christopher L Antos

Joseph A Hill

Eric N Olson

Affiliations

Soon will be listed here.

Abstract

The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are refractory to hypertrophic signaling and inhibit cardiomyocyte hypertrophy. Conversely, mutant mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals and exhibit stress-dependent cardiomegaly. Thus, class II HDACs act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.

Citing Articles

Enzyme-independent functions of HDAC3 in the adult heart.

Qian S, Zhang C, Li W, Song S, Lin G, Cheng Z bioRxiv. 2025; .

PMID: 39803453 PMC: 11722435. DOI: 10.1101/2024.12.29.630635.

Epigenetics in Heart Failure.

Ho J, Jou E, Khong P, Foo R, Sia C Int J Mol Sci. 2024; 25(22).

PMID: 39596076 PMC: 11593553. DOI: 10.3390/ijms252212010.

Epigenetics of cardiomyopathies: the next frontier.

Hajdarpasic A, Tukker M, Rijdt W, Mohamedhoesein S, Meijers W, Caliskan K Heart Fail Rev. 2024; 30(1):257-270.

PMID: 39586986 PMC: 11646213. DOI: 10.1007/s10741-024-10460-4.

Sex difference in human diseases: mechanistic insights and clinical implications.

Shi Y, Ma J, Li S, Liu C, Liu Y, Chen J Signal Transduct Target Ther. 2024; 9(1):238.

PMID: 39256355 PMC: 11387494. DOI: 10.1038/s41392-024-01929-7.

Understanding the roles of salt-inducible kinases in cardiometabolic disease.

Shi F Front Physiol. 2024; 15:1426244.

PMID: 39081779 PMC: 11286596. DOI: 10.3389/fphys.2024.1426244.

References

Naya F, Wu C, Richardson J, Overbeek P, Olson E . Transcriptional activity of MEF2 during mouse embryogenesis monitored with a MEF2-dependent transgene. Development. 1999; 126(10):2045-52. DOI: 10.1242/dev.126.10.2045. View

Zhou X, Marks P, Rifkind R, Richon V . Cloning and characterization of a histone deacetylase, HDAC9. Proc Natl Acad Sci U S A. 2001; 98(19):10572-7. PMC: 58507. DOI: 10.1073/pnas.191375098. View

Frey N, McKinsey T, Olson E . Decoding calcium signals involved in cardiac growth and function. Nat Med. 2000; 6(11):1221-7. DOI: 10.1038/81321. View

Grozinger C, Schreiber S . Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc Natl Acad Sci U S A. 2000; 97(14):7835-40. PMC: 16631. DOI: 10.1073/pnas.140199597. View

Grozinger C, Schreiber S . Deacetylase enzymes: biological functions and the use of small-molecule inhibitors. Chem Biol. 2002; 9(1):3-16. DOI: 10.1016/s1074-5521(02)00092-3. View

Zhang C, McKinsey T, Lu J, Olson E . Association of COOH-terminal-binding protein (CtBP) and MEF2-interacting transcription repressor (MITR) contributes to transcriptional repression of the MEF2 transcription factor. J Biol Chem. 2000; 276(1):35-9. DOI: 10.1074/jbc.M007364200. View

McKinsey T, Zhang C, Olson E . MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci. 2002; 27(1):40-7. DOI: 10.1016/s0968-0004(01)02031-x. View

Youn H, Chatila T, Liu J . Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J. 2000; 19(16):4323-31. PMC: 302027. DOI: 10.1093/emboj/19.16.4323. View

McKinsey T, Zhang C, Olson E . Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci U S A. 2000; 97(26):14400-5. PMC: 18930. DOI: 10.1073/pnas.260501497. View

10.

Chien K . Stress pathways and heart failure. Cell. 1999; 98(5):555-8. DOI: 10.1016/s0092-8674(00)80043-4. View

11.

Zhang C, McKinsey T, Olson E . The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci U S A. 2001; 98(13):7354-9. PMC: 34672. DOI: 10.1073/pnas.131198498. View

12.

Black B, Olson E . Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol. 1999; 14:167-96. DOI: 10.1146/annurev.cellbio.14.1.167. View

13.

Kirchhefer U, Schmitz W, Scholz H, Neumann J . Activity of cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human hearts. Cardiovasc Res. 1999; 42(1):254-61. DOI: 10.1016/s0008-6363(98)00296-x. View

14.

Passier R, Zeng H, Frey N, Naya F, Nicol R, McKinsey T . CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest. 2000; 105(10):1395-406. PMC: 315462. DOI: 10.1172/JCI8551. View

15.

Liang Q, de Windt L, Witt S, Kimball T, Markham B, Molkentin J . The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem. 2001; 276(32):30245-53. DOI: 10.1074/jbc.M102174200. View

16.

Hill J, Karimi M, Kutschke W, Davisson R, Zimmerman K, Wang Z . Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation. 2000; 101(24):2863-9. DOI: 10.1161/01.cir.101.24.2863. View

17.

Impey S, Fong A, Wang Y, Cardinaux J, Fass D, Obrietan K . Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron. 2002; 34(2):235-44. DOI: 10.1016/s0896-6273(02)00654-2. View

18.

Johnson C, Turner B . Histone deacetylases: complex transducers of nuclear signals. Semin Cell Dev Biol. 1999; 10(2):179-88. DOI: 10.1006/scdb.1999.0299. View

19.

Molkentin J, Lu J, Antos C, Markham B, Richardson J, Robbins J . A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93(2):215-28. PMC: 4459646. DOI: 10.1016/s0092-8674(00)81573-1. View

20.

Lu J, McKinsey T, Nicol R, Olson E . Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases. Proc Natl Acad Sci U S A. 2000; 97(8):4070-5. PMC: 18151. DOI: 10.1073/pnas.080064097. View