Conserved Transcriptomic Signatures of Sirt6 Activity: A Cross-Species RNA-seq Meta-analysis

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Sirtuin 6 (Sirt6) is an NAD+-dependent deacetylase regulating critical cellular processes.
• Understanding Sirt6's transcriptional targets is key to its roles in aging, metabolism, and cancer.
• Previous studies lacked a systematic analysis of Sirt6-mediated gene expression changes.

Purpose of the Study:

• To perform a comprehensive meta-analysis of Sirt6-regulated genes across multiple mammalian datasets.
• To identify conserved Sirt6 regulatory pathways in *Drosophila melanogaster*.
• To establish consensus on Sirt6 target genes and pathways.

Main Methods:

• Meta-analysis of 19 mammalian RNA-sequencing (RNA-seq) datasets with Sirt6 level alterations.
• Gene Set Enrichment Analysis and pathway analysis of differentially expressed genes.
• RNA-seq meta-analysis in *Drosophila melanogaster* with Sirt6 perturbation.

Main Results:

• Consistent gene expression changes observed upon Sirt6 level reduction in mammals.
• Increased expression of immune response and ribosomal protein genes.
• Decreased expression of lipid oxidation and oxidative phosphorylation genes.
• Novel Sirt6 regulation identified in Extracellular Matrix and E2F target genes.
• Conserved regulatory patterns, including lipid oxidation, found between mammals and *Drosophila*.

Conclusions:

• This meta-analysis provides consensus on conserved and novel transcriptional pathways regulated by Sirt6.
• Sirt6 plays a crucial role in regulating metabolism, immune response, and cellular stress.
• Findings highlight Sirt6 as a potential therapeutic target for age-related diseases.