TY - JOUR
T1 - Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy
AU - Zhang, Chun-Li
AU - McKinsey, Timothy A.
AU - Chang, Shurong
AU - Antos, Christopher L.
AU - Hill, Joseph A
AU - Olson, Eric N
N1 - Funding Information:
We are grateful to Yin-Chai Cheah for blastocyst injections, Hartmut Weiler for assistance with gene targeting, Robert Gerard for assistance with viruses, and Stuart Schreiber for providing HDAC plasmids. We thank James Richardson, Jeff Starks, and John Shelton for histological sections, and Alisha Tizenor for graphics. This work was supported by grants from the National Institutes of Health, the D.W. Reynolds Clinical Cardiovascular Research Center, the Texas Advanced Technology Program, and the Robert A. Welch Foundation to E.N.O. T.A.M. is a Pfizer Fellow of the Life Sciences Research Foundation.
PY - 2002/8/23
Y1 - 2002/8/23
N2 - 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.
AB - 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.
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U2 - 10.1016/S0092-8674(02)00861-9
DO - 10.1016/S0092-8674(02)00861-9
M3 - Article
C2 - 12202037
AN - SCOPUS:0037162697
SN - 0092-8674
VL - 110
SP - 479
EP - 488
JO - Cell
JF - Cell
IS - 4
ER -