Chromosomal characterization and localization of the NAD+-dependent histone deacetylase gene sirtuin 1 in the mouse.

ABSTRACT

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which belongs to the silent information regulator 2 (Sir2) family of histone deacetylases (HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, the cell cycle, microtubule organization, and in the regulation of aging. We isolated and characterized the murine Sirt1 genomic sequence, which spans 19,910 bp and has one single genomic locus. Determination of the exon-intron splice junctions established that SIRT1 is encoded by 9 exons ranging in size from 80 bp (exon 6) to 1,927 bp (exon 9). Characterization of the 5' flanking genomic region, which precedes the Sirt1 open reading frame, revealed a number of NFkappaB and GATA transcription factor binding sites in addition to a 393-bp CpG island. The 3,882-bp murine Sirt1 transcript has an open reading frame of 2,211 bp and encodes a 737 aa protein with a predicted molecular weight of 80.4 kDa and an isoelectric point of 4.60. Next to this transcript, a shorter, 3,765 bp splice variant with an open reading frame of 2,094 bp, that lacks exon 2 and encodes a 698 aa protein with a predicted molecular weight of 76.0 kDa and an isoelectric point of 4.62 has been reported. Fluorescence in situ hybridization analysis identified a single genomic locus for the murine Sirt1 gene on chromosome 10 B4 and is neighbored by the Herc4 and Dnajc12 genes.