Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy

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.

Lamr1 functional retroposon causes right ventricular dysplasia in mice

“…The stochastic competition between such factors as LAMR1-TP1 and HP1-α may determine the fate of the heterochromatin plasticity that is involved in regulating the fate of cells. Class II histone deacetylase acts as a signal-responsive suppressor of the transcriptional events governing cardiac hypertrophy and heart failure 27 . HP1 can link with class II histone deacetylase 28 and thus may modify cardiac cell metabolism.…”

Class II histone deacetylases: versatile regulators

“…The sequences of the phosphorylation sites in class IIa HDACs are closely related to consensus phosphorylation sites for Ca 2þ /CaM-dependent protein kinases (CaMKs) [43], and CaMK-mediated phosphorylation of HDAC4, -5, -7 and -9 promotes their association with 14-3-3 proteins and stimulates their nuclear export to the cytoplasm [21 -24,44]. Recent experiments in cardiomyocytes indicate that an unidentified HDAC kinase targets the same phosphorylation sites in class IIa HDACs in response to hypertrophic signals [45].…”

“…A phosphorylation mutant of HDAC9 in the CaMK IV sites inhibits the myogenic program [24]. Conversely, HDAC9-deficient mice show a striking susceptibility to stress-induced cardiac hypertrophy [45]. In cardiomyocytes, phosphorylation mutants of HDAC5 or MITR block the induction of hypertrophy-associated genes in response to phenylephrine [45].…”

“…Conversely, HDAC9-deficient mice show a striking susceptibility to stress-induced cardiac hypertrophy [45]. In cardiomyocytes, phosphorylation mutants of HDAC5 or MITR block the induction of hypertrophy-associated genes in response to phenylephrine [45]. These observations suggest that class IIa HDACs are master regulators of myocyte development.…”

Developmental potential of Gcn5−/− embryonic stem cells in vivo and in vitro

“…Data so far indicate that individual HATs and HDACs have specialized functions in cell and tissue differentiation. Class II HDACs (HDAC9 and HDAC5), for example, limit stress-induced cardiac hypertrophy (McKinsey et al, 2001;Zhang et al, 2002;Song et al, 2006), whereas HDAC4 limits chondrocyte hypertrophy and endochondral bone formation (Vega et al, 2004). Loss of either of p300 or CBP, two highly related HATs, leads to mid-gestation embryonic death (Yao et al, 1998).…”