Cloning and Functional Characterization of HDAC11, a Novel Member of the Human Histone Deacetylase Family

Abstract

We have cloned and characterized a human cDNA that belongs to the histone deacetylase family, which we designate as HDAC11. The predicted HDAC11 amino acid sequence reveals an open reading frame of 347 residues with a corresponding molecular mass of 39 kDa. Sequence analyses of the putative HDAC11 protein indicate that it contains conserved residues in the catalytic core regions shared by both class I and II mammalian HDAC enzymes. Putative orthologues of HDAC11 exist in primate, mouse, Drosophila, and plant. Epitopetagged HDAC11 protein expressed in mammalian cells displays histone deacetylase activity in vitro. Furthermore, HDAC11's enzymatic activity is inhibited by trapoxin, a known histone deacetylase inhibitor. Multiple tissue Northern blot and real-time PCR experiments show that the high expression level of HDAC11 transcripts is limited to kidney, heart, brain, skeletal muscle, and testis. Epitope-tagged HDAC11 protein localizes predominantly to the cell nucleus. Co-immunoprecipitation experiments indicate that HDAC11 may be present in protein complexes that also contain HDAC6. These results indicate that HDAC11 is a novel and unique member of the histone deacetylase family and it may have distinct physiological roles from those of the known HDACs.In eukaryotes, DNA is packaged into chromatin structures, whose basic unit is the nucleosome. Each nucleosome consists of ϳ148 bp DNA wrapping around a core histone octamer, which includes two copies each of H2A, H2B, H3, and H4 (1). The packaging of DNA generally creates a repressive environment for gene expression; therefore, transcriptional activation of many genes requires chromatin modifications, such as the reversible acetylation of core histones. Transfer of an acetyl group from acetyl-CoA onto the ⑀-amino group of various lysine residues in the NH 2 -terminal tails of core histones is a ubiquitous process found in all eukaryotes examined. The steady state level of acetylation is controlled by the competing activities of histone acetyltransferases and histone deacetylases (HDACs).1 In general, hypoacetylated chromatin is associated with gene silencing, whereas hyperacetylation correlates with gene activation (2-5). However, recent studies have shown that histone deacetylation can also play a significant role in transcriptional activation. For example, inhibition of HDACs by trichostatin A or trapoxin both activates and silences a small fraction of cellular genes in mammalian cells (6, 7). Furthermore, mutation of the yeast histone deacetylases RPD3 and SIN3 shows that both genes are required to fully activate or to repress specific promoters (6, 8 -10). Finally, there is increasing evidence to support the idea that acetylation/deacetylation of non-histone proteins may also function in activation as well as repression of transcription (11)(12)(13)(14).Since the discovery of histone deacetylase RPD3 in Saccharomyces cerevisiae, numerous HDACs have been identified in mammalian cells, and are grouped into three classes based on sequence homologies. Members of...

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Histone deacetylase inhibitors: molecular mechanisms of action

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Class II histone deacetylases: versatile regulators

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“…Organization of class II histone deacetylases (HDACs) (a) Phylogenic tree analysis of known mammalian HDACs and their yeast orthologs for the HDAC class I and II families (adapted from Ref. [11]). The human proteins are preceded by h, the yeast proteins by y and the prokaryotic proteins by pro.…”