The Histone Deacetylase 9 Gene Encodes Multiple Protein Isoforms

Abstract

Histone deacetylases (HDACs) perform an important function in transcriptional regulation by modifying the core histones of the nucleosome. We have now fully characterized a new member of the Class II HDAC family, HDAC9. The enzyme contains a conserved deacetylase domain, represses reporter activity when recruited to a promoter, and utilizes histones H3 and H4 as substrates in vitro and in vivo. HDAC9 is expressed in a tissue-specific pattern that partially overlaps that of HDAC4. Within the human hematopoietic system, expression of HDAC9 is biased toward cells of monocytic and lymphoid lineages. The HDAC9 gene encodes multiple protein isoforms, some of which display distinct cellular localization patterns. For example, full-length HDAC9 is localized in the nucleus, but the isoform lacking the region encoded by exon 7 is in the cytoplasm. HDAC9 interacts and co-localizes in vivo with a number of transcriptional repressors and co-repressors, including TEL and N-CoR, whose functions have been implicated in the pathogenesis of hematological malignancies. These results suggest that HDAC9 plays a role in hematopoiesis; its deregulated expression may be associated with some human cancers.

Class IIa histone deacetylases: regulating the regulators

“…The adapter domain of class IIa HDACs contains specific residues that are subjected to various posttranslational modifications, such as proteolytic cleavage (Bakin and Jung, 2004;Liu et al, 2004;Paroni et al, 2004), ubiquitination , sumoylation (Kirsh et al, 2002;Petrie et al, 2003) and most importantly phosphorylation. In response to various stimuli, a set of serine residues in the adapter domain of class IIa HDACs is phosphorylated, creating docking sites for the 14-3-3 proteins (Grozinger and Schreiber, 2000;Wang et al, 2000).…”

“…HDAC4 and -9 are subject to sumoylation, at a lysine residue also conserved in HDAC5 (Tatham et al, 2001;Kirsh et al, 2002;Petrie et al, 2003). SUMO is believed to alter the interaction properties of its target, often affecting its localization within the cell (Seeler and Dejean, 2001).…”

“…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.…”

Promotion of Anchorage-independent Growth by Cytoplasmic and Nuclear Histone Deacetylase 9

“…Human Hdac9 cDNAs have been cloned (AY032737, AY032738, and AY197371) and their predicted amino acid sequences share 92% identity with rat HDAC9FL. 15,19) Isoforms lacking the region encoded by exon 7 have also been identified in humans and found to be located in the cytoplasm. We showed that rat HDAC9∆7 too was selectively expressed in the cytoplasm, suggesting the function of the NLS encoded in exon 7 to be conserved in humans and rats.…”

“…15) When we started cloning Hdac9 cDNA, two predicted rat Hdac9 cDNA sequences (XM 576017 and XM 234063) were registered in the database, but they did not overlap. To isolate the full-length ORF, we performed 5 -RACE and RT-PCR.…”