SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
Sirtuins, a class of highly conserved histone/protein deacetylases, are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled both transcriptionally, translationally and via localization within the cell. While Sirtuin proteins are associated with aging, how their levels are regulated during aging across cell types and how they elicit tissue-specific age-related cellular changes are unclear. Here, we demonstrate that SIRT7 is targeted for degradation during senescence and liver aging. To uncover the significance and regulation of SIRT7 loss, we performed proteomics analysis and found that the E3 Ligase TRIP12 reduces SIRT7 levels during senescence. We identified the HMG box transcription factor NUCKS1 as a new SIRT7 interactor. We found that NUCKS1 is recruited onto chromatin during senescence, mediated by SIRT7 loss and accompanied by increased NUCKS1 acetylation. Depletion of NUCKS1 delayed senescence upon DNA damage leading to reduced inflammatory gene expression. Examination of transcriptional regulation by NUCKS1 during senescence revealed target genes of transcription factors NFKB1, RELA, and CEBP?—all previously associated with senescence. Consistently, in Sirt7 KO mouse liver and in naturally aged livers, NUCKS1 was recruited to chromatin, bound at promoters and enhancers of age-related genes, including transcription factor Rela, and these bound sites had increased accessibility during aging. Overall, our results uncover NUCKS1 as a novel interactor of SIRT7, showing that proteosomal loss of SIRT7 during senescence and liver aging promotes chromatin binding of acetylated NUCKS1 to induce metabolic and inflammatory genes. Overall design: Investigate the function of SIRT7 mediated regulation of NUCKS1 in senescence and liver aging. To assess SIRT7 function during liver aging, RNA-sequencing of WT or SIRT7 KO livers was performed on young and aged livers. To determine NUCKS1 role in eliciting senescence associatd gene expression, RNA-sequencing of shRNA targeting control or NUCKS1 was done in proliferating and senescent IMR90 lung fibroblasts.