Cloning and structural characterization of the human histone deacetylase 6 gene

Histone deacetylases (HDACs) play a central role in the modification of chromatin structure and thus in the regulation of transcription and cellular differentiation. Based on structural and functional similarities, mammalian histone deacetylases may be grouped into three categories, class I HDACs, which are homologs of the yeast histone deacetylase RPD3, class II HDACs, which share a significant degree of homology with the yeast histone deacetylase HDA1 and class III HDACs which are closely related to the yeast SIR2 protein. We have isolated and characterized the human HDAC6 genomic sequence, which spans a region of 21,923 bp and which has one single genomic locus. Determination of the exon-intron splice junctions established that HDAC6 is encoded by 28 exons ranging in size from 41 bp (exon 5) to 677 bp (exon 24). Characterization of the 5' flanking genomic region, which precedes the HDAC6 open reading frame, revealed a TATA- and CCAAT-boxless promoter that contains a 1 kb CpG island. The 3,648 bp human HDAC6 mRNA encodes a 1,215 aa protein with a predictive molecular weight of 131.4 kDa. Fluorescence in situ hybridization analysis localized the human HDAC6 gene to the subband border of chromosome Xp11.22-23, a region which is characterized by frequent gains and losses of chromosomal material in several types of cancer and neurological disorders.