Isolation and Characterization of cDNAs Corresponding to an Additional Member of the Human Histone Deacetylase Gene Family

Abstract

Several human cDNAs encoding a histone deacetylase protein, HDAC3, have been isolated. Analysis of the predicted amino acid sequence of HDAC3 revealed an open reading frame of 428 amino acids with a predicted molecular mass of 49 kDa. The HDAC3 protein is 50% identical in DNA sequence and 53% identical in protein sequence compared with the previously cloned human HDAC1. Comparison of the HDAC3 sequence with human HDAC2 also yielded similar results, with 51% identity in DNA sequence and 52% identity in protein sequence. The expressed HDAC3 protein is functionally active because it possesses histone deacetylase activity, represses transcription when tethered to a promoter, and binds transcription factor YY1. Similar to HDAC1 and HDAC2, HDAC3 is ubiquitously expressed in many different cell types.The organization of chromatin structure is a fundamental and significant component of transcriptional regulation in all eukaryotic cells. Transcriptionally active or repressed chromatin is determined, at least in part, by the modification of histones. For example, hyperacetylation of histones generally leads to an increase in transcription, whereas hypoacetylation of histones appears to have the opposite effect (reviewed in Refs. 1-4). Nuclear histone acetyltransferases such as transcription factors GCN5, PCAF, p300/CBP, and TAF II 230/250 have been identified from different organisms (5-9).Several yeast and mammalian histone deacetylases have been identified, and their corresponding genes have been cloned (10 -12). In yeast, the HDA1 protein, which shares sequence similarity to RPD3, is a subunit of a large histone deacetylase complex HDA. RPD3 is also associated with another yeast histone deacetylase complex HDB. Using a trapoxin (an inhibitor of histone deacetylase) affinity matrix, Taunton et al. (10) purified and cloned a human 55-kDa protein related to the yeast protein RPD3. Immunoprecipitation of this 55-kDa protein, HDAC1 (also called HD1), showed that it contains histone deacetylase activity. A second human histone deacetylase protein, HDAC2, with high homology to yeast RPD3 was identified based on a yeast two-hybrid trap experiment with the YY1 transcription factor as a bait (11). YY1 negatively regulates transcription by tethering HDAC2 to DNA as a corepressor. Both HDAC1 and HDAC2 exist in a complex with the corepressor mSIN3 and mediate Mad transcriptional repression (13-15). In addition, HDAC1 and HDAC2 are essential components of two thyroid hormone receptor corepressors, N-CoR and SMRT (16 -18). HDAC1 is also an important factor that represses transactivation by progesterone receptor (19).The yeast RPD3 protein was originally identified in genetic screens for transcriptional repressors (20). Besides human and mouse, highly homologous yeast RPD3 sequences have been identified in Drosophila (21), Caenorhabditis elegans (X78454 and 1176665), and Xenopus laevis (gi:576995). Currently, it has not yet been established whether the C. elegans or X. laevis RPD3-related proteins have histone deacetylase activities o...

HDAC3: taking the SMRT-N-CoRrect road to repression

“…Similar to HDACs 1 and 2, HDAC3 is also ubiquitously expressed. As expected by the sequence identity, early functional analysis of the HDAC3 protein revealed common features with HDACs 1 and 2, namely deacetylation of histone substrates, transcriptional repression when targeted to promoters, as well as physical association with the DNA-binding factor YY1 (Yang et al, 1997;Dangond et al, 1998;Emiliani et al, 1998). Together, these findings suggested that this ubiquitously expressed protein could be involved in the regulation of mammalian gene expression.…”

“…Its open reading frame predicted a 428 aa protein, with an estimated molecular mass of 49 kDa. Human HDAC3 is 53% identical with human HDAC1 and 52% identical with human HDAC2 at the amino acid level (Yang et al, 1997;Dangond et al, 1998). This similarity led to the classification of the above three proteins into one family.…”

“…Initially cloned based on sequence similarity with the previously identified histone deacetylases (HDACs) 1 and 2, HDAC3 was the third mammalian deacetylase to be identified (Yang et al, 1997;Dangond et al, 1998;Emiliani et al, 1998). Its open reading frame predicted a 428 aa protein, with an estimated molecular mass of 49 kDa.…”

“…On the other hand, HDAC3 contains an intriguingly variable C terminus, with no apparent similarity with other HDACs. This observation led to the hypothesis that HDAC3 may have some unique properties and may not be completely redundant with the other HDACs (Yang et al, 1997). This is also suggested by the differential localization of HDAC3, which, unlike the predominantly nuclear HDACs 1 and 2, can be found in the nucleus, the cytoplasm and at the plasma membrane (Takami and Nakayama, 2000;Longworth and Laimins, 2006).…”

The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoR

“…E1A interacts with various chromatin modifying proteins, (reviewed by Mymryk and Smith, 1997), some of which display histone acetyltransferase (HAT) activity, such as the transcriptional coactivators CBP/p300 (Ogryzko et al, 1996) and TAF II -250 (Geisberg et al, 1995;Mizzen et al, 1996). Other E1A binding proteins are directly associated with histone deacetylase proteins (HDAc's), like the Rb family of transcriptional repressors (Luo et al, 1998;Brehm et al, 1998;Magnaghi et al, 1998;Ferreira et al, 1998) and the transcriptional regulators YY-1 (Lee et al, 1995;Lewis et al, 1995;Yang et al, 1997) and CtBP (Schaeper et al, 1995;Sundqvist et al, 1998).…”