HDAC4 deacetylase associates with and represses the MEF2 transcription factor

Abstract

The acetylation state of histones can influence transcription. Acetylation, carried out by acetyltransferases such as CBP/p300 and P/CAF, is commonly associated with transcriptional stimulation, whereas deacetylation, mediated by the three known human deacetylases HDAC1, 2 and 3, causes transcriptional repression. The known human deacetylases represent a single family and are homologues of the yeast RPD3 deacetylase. Here we identify and characterize HDAC4, a representative of a new human histone deacetylase family, which is homologous to the yeast HDA1 deacetylase. We show that HDAC4, unlike other deacetylases, shuttles between the nucleus and the cytoplasm in a process involving active nuclear export. In the nucleus, HDAC4 associates with the myocyte enhancer factor MEF2A. Binding of HDAC4 to MEF2A results in the repression of MEF2A transcriptional activation, a function that requires the deacetylase domain of HDAC4. These results identify MEF2A as a nuclear target for HDAC4-mediated repression and suggests that compartmentalization may be a novel mechanism for controlling the nuclear activity of this new family of deacetylases.

Class II histone deacetylases: versatile regulators

“…All class IIa HDACs shuttle between the nucleus and the cytoplasm [6,20,21,23,26,[38][39][40]. Class IIa HDACs bind to 14-3-3 proteins, a family of highly conserved acidic proteins (reviewed in Ref.…”

“…Class II HDACs, the subject of this review, are homologous to yHDA1 and are subdivided into two subclasses, IIa (HDAC4, -5, -7 and -9 and its splice variant MITR) and IIb (HDAC6 and HDAC10), based on sequence homology and domain organization (Fig. 1a,b) [4][5][6][7][8][9][10][11][12]. Whereas class I and II HDACs and their Fig.…”

“…The class IIa HDACs: HDAC4, -5, -7 and -9 HDAC4, -5, -7 and -9 contain a highly conserved C-terminal catalytic domain (, 420 amino acids) homologous to yHDA1 and an N-terminal domain with no similarity to other proteins (Fig. 1b) [4][5][6][7]13]. MITR, a splice variant of HDAC9, consists of only its N-terminus without an HDAC domain.…”

Class IIa histone deacetylases: regulating the regulators

“…Together with HDAC1, four additional human Rpd3 orthologs, HDAC2, -3, -8 and -11 make up the mammalian class I HDAC family (Marks et al, 2003). Class II HDACs (HDAC4, are defined based on their sequence homology with Hda1 in Saccharomyces cerevisiae (Fischle et al, 1999(Fischle et al, , 2001(Fischle et al, , 2002Grozinger et al, 1999;Miska et al, 1999;Verdel and Khochbin, 1999;Wang et al, 1999;Kao et al, 2000;Zhou et al, 2001;Guardiola and Yao, 2002;Tong et al, 2002;Petrie et al, 2003). The Hda1-like sequences of class II HDACs correspond to their catalytic domain.…”

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

“…Interestingly, most patients harboring recessive RYR1 mutations exhibit a 6-16 fold increase in class II histone de-acetylase protein content (HDAC-4 and HDAC-5) and hypermethylation of (at least) a CpG island within the RYR1 gene. Class II HDACs can bind to and sequester the muscle transcription factor mef-2 [58], thus one would expect that an increase in HDAC-4/5 expression would prevent the transcription of mef-2 dependent genes. The transcription of miR-1 and miR-133 has been shown to be mef-2 dependent [59] and the 5 region of the RYR1 contains a mef-2 binding domain [60].…”