Acetylation of histones by histone

Acetylation of histones by histone acetyltransferases stimulates gene expression by relaxing PPDA structure, allowing access of transcription factors to DNA, whereas deacetylation of histones by histone deacetylases promotes chromatin condensation and transcriptional repression. Recent studies demonstrate histone acetylation/deacetylation to be a nodal point for the control of cardiac growth and gene expression in response to acute and chronic stress stimuli [25]. There are currently 18 known human HDACs, which fall into 3 classes based on their homology with 3 distinct yeast HDACs. Among them, class II HDACs have been shown to repress the growth of myocytes [6], whereas there is also increasing evidence that class I HDACs might exert opposite effects and promote cellular growth [3], [26]. Mice lacking either HDAC5 or HDAC9 are viable and there is no evidence of cardiac abnormalities at early age. However, at about 6months of age, mutant animals develop spontaneous cardiac hypertrophy that appears to reflect sensitization to age-related cardiac insults [6]. HDAC5 and HDAC9 mutant mice also develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals [5], [6]. HDAC2 deficiency or chemical HDAC inhibition prevents the re-expression of fetal genes and attenuates the cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy is associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3β (GSKβ) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, HDAC2 transgenic mice have augmented hypertrophy associated with inactivated Gsk3β. Chemical inhibition of activated Gsk3β allows HDAC2-deficient adults to become sensitive to hypertrophic stimulation [3]. The functions of NAD+-dependent class III HDACs or the Sirtuins in hypertrophy are different from each other. The function of SIRT1 in the heart is still under debate. It seems that its negative or positive role in cardiac hypertrophy depends largely upon the individual effect factors [7], [8]. The hearts of SIRT2 knockout mice, and wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury [27]. Interestingly, SIRT3, SIRT6 and SIRT7 could protect hearts from hypertrophy by deacetylating Foxo3a, blocking IGF-Akt signaling or deacetylating p53 respectively [9], [10], [11]. Those findings indicate that different HDACs have different roles in hypertrophic cardiopathy, and imbalance of HDACs leads to the development of cardiac hypertrophy. Interestingly, the HDACs can influence each other in the progress of cardiac growth. The significance of interclass crosstalk in the development of cardiac hypertrophy has recently been identified. Eom et al. [13] showed that the balance of HDAC2 acetylation is regulated by PCAF and HDAC5 in the development of cardiac hypertrophy. During cardiac hypertrophy, HDAC5 is phosphorylated and is translocated to the cytoplasm, which leads to the acetylation of HDAC2 and subsequent cardiac hypertrophy. Importantly, the interaction between HDACs and HATs has also been revealed in that study. Current studies indicate that HATs are pro-hypertrophic. Among the five families, the PCAF of the GNAT family and CREB-binding protein (CBP) p300 have been shown to block the development of pathological hypertrophy. Both p300 and PCAF successfully induce cardiac hypertrophy either by transcriptional activation of heart-specific genes or by acetylation of non-histone substrates such as GATA4 [28], [29]. In addition, PCAF, but not p300, induced acetylation and following activates HDAC2 when hypertrophy occurred [13]. Here in this study, we identified MOF, another class of HAT, as an anti-hypertrophic factor. MOF is the first HAT that is identified to be a negative mediator of cardiac hypertrophy. These findings strongly indicated that HATs exhibit diverse functions in hypertrophic cardiopathy. The dynamic acetylation and deacetylation of histones play essential role in hypertrophy Imbalance of histone acetylation triggers the expression of hypertrophic fetal genes. The interaction between HDACs and HATs critically controls the modification statue of histone, and orchestrates the response to hypertrophic stimuli and the development of cardiac hypertrophy.