HDAC4, a Human Histone Deacetylase Related to Yeast HDA1, Is a Transcriptional Corepressor

Abstract

Histone acetylation plays an important role in regulating chromatin structure and thus gene expression. Here we describe the functional characterization of HDAC4, a human histone deacetylase whose C-terminal part displays significant sequence similarity to the deacetylase domain of yeast HDA1. HDAC4 is expressed in various adult human tissues, and its gene is located at chromosome band 2q37. HDAC4 possesses histone deacetylase activity intrinsic to its C-terminal domain. When tethered to a promoter, HDAC4 represses transcription through two independent repression domains, with repression domain 1 consisting of the N-terminal 208 residues and repression domain 2 containing the deacetylase domain. Through a small region located at its N-terminal domain, HDAC4 interacts with the MADS-box transcription factor MEF2C. Furthermore, HDAC4 and MEF2C individually upregulate but together downmodulate c-jun promoter activity. These results suggest that HDAC4 interacts with transcription factors such as MEF2C to negatively regulate gene expression.In eukaryotic cells, genetic information is packaged into chromatin, a highly organized DNA-protein complex which controls gene activities. A central question in studying eukaryotic gene regulation is how the generally repressive chromatin structure is regulated when necessary. In the past several years, three regulatory mechanisms have been recognized: DNA methylation, posttranslational modifications of histones, and ATP-dependent chromatin remodeling (53,55,57). The most extensively studied form of posttranslational modifications of histones is acetylation of ε-amino groups of lysine residues located at the flexible N-terminal tails of core histones (53, 55). The level of histone acetylation at a given region of chromatin correlates well with its transcriptional activity (39). Mechanistically, histone acetylation affects nucleosome stability and/or internucleosomal interaction (2, 29). The dynamic level of histone acetylation in vivo is maintained through opposing actions of histone acetyltransferases and deacetylases. Several known transcriptional coactivators possess intrinsic histone acetyltransferase activity (14,27,49,57).The first histone deacetylase, originally called HD1 (histone deacetylase 1) and later renamed HDAC1 (histone deacetylase 1), was cloned from mammalian cells (18, 50). HDAC1 was found to be highly homologous to the known yeast transcriptional coregulator RPD3 (50). Two HDAC1 homologs (HDAC2 and HDAC3) have been cloned from human cDNA libraries (10,58,59). Transcriptional repressors recruit RPD3 or HDAC1 to -3 to downregulate transcription (reviewed in references 41 and 56). The deacetylase activity of HDAC1 and RPD3 has been found to be important for transcriptional repression (18, 24), suggesting that histone deacetylation directly leads to transcriptional repression. Consistent with this contention, recruitment of RPD3 by the yeast repressor Ume6 leads to local histone deacetylation and formation of a highly localized domain of repressed chromatin in vivo...

Class II histone deacetylases: versatile regulators

“…HDAC4, -5, -7 and -9 interact with MEF2 proteins through a highly conserved 17 amino acid motif located in their N-termini [7,23,38,65,66]. Expression of an HDAC -VP16 fusion protein, in which the VP16 activation domain replaces the catalytic domain of HDAC4 or -5, enhances myogenic conversion [47].…”

“…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

“…This might explain why, in contrast to class I HDACs, researchers in the field have remained remarkably unsuccessful at obtaining enzymatically active class IIa HDACs in recombinant forms in vitro (Hassig et al, 1998;Hu et al, 2000). When successful, these attempts have mainly yielded protein preparations with low specific activity, especially when compared to the corresponding protein analysed in vivo (Wang et al, 1999). Indeed, when expressed as an isolated subdomain the C-terminal region of class IIa HDACs associates with full-HDAC activity in vivo (Wang et al, 1999;Fischle et al, 2001Fischle et al, , 2002.…”

“…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.…”