Sirtuin gene isoforms and genomic sequences of mouse and humans: Divergence across species

AbstractBackgroundThere are seven sirtuin genes in the mammalian genome. Each sirtuin gene contains multiple exons, and is likely to undergo alternative splicing, thereby increasing sirtuin gene diversity. Since the alternatively spliced isoforms tend to increase with advancing age, it is important to study the effect of sequence change on isoform function. Additionally, the divergence of isoform patterns between human and mouse will help us to properly interpret the findings from animal models, especially in age-related studies. Recently, more than 20 human sirtuin isoforms have been identified, but whether the mouse genome might have similar isoforms remains incompletely established.MethodsThe mRNA, protein and genomic DNA sequences of mouse sirtuin genes, as well as the transcription factor binding sites, including that of SRF, were analyzed. A cellular stress model with serum deprivation and restoration was used to reflect the blood supply and nutrients level changes in the ischemia and reperfusion condition, and the expression of sirtuin isoform was assessed.ResultsHere, we report the identification of 15 mouse sirtuin isoforms, of which over half have not been previously reported. Exon skipping was the main event, which led to domain losses in the nuclear localization signal, nucleolar localization signal, and/or the mitochondrial targeting sequence among sirtuin isoforms. Among 7 sirtuin genes, 6 mouse sirtuin genes had different exon numbers versus that of human sirtuin genes. Only the sirtuin-2 gene had the same number of exons in both human and mouse. However, there were differences in the sirtuin-2 gene isoforms and the regulatory domains between the two species. The expression of sirtuin gene isoforms under serum stress was also different.ConclusionsAlternative splicing increases both sirtuin transcriptome and proteome diversity. However, the sirtuin isoforms were not well conserved between human and mouse, which should be taken into consideration when extrapolating animal studies for human physiology and pathology. Our results will help to elucidate the role of sirtuin genes in the regulation of cellular stress response, including ischemia and reperfusion. We propose that the existence of the CArG and CArG-like sequences in sirtuin genes may imply a role for SRF in the sirtuin family transcriptional regulation.