SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

Sirtuins enzymes are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled but how sirtuin levels are regulated during aging and how they elicit tissue-specific cellular changes are unclear. We demonstrate that SIRT7 is targeted for degradation during senescence and is regulated by E3 Ligase TRIP12. We identified transcription factor NUCKS1 interacts with SIRT7 and is recruited onto chromatin during senescence. This is mediated by SIRT7 loss and subsequent increase of NUCKS1 acetylation. NUCKS1 depletion delayed senescence leading to reduced inflammatory gene expression associated with RELA, and CEBP. In Sirt7 KO mouse and aged livers, NUCKS1 was bound at promoters and enhancers of age-related genes and these regions gain accessibility during aging. Overall, our results uncover NUCKS1 as a interactor of SIRT7 and proteosomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.

沉默信息调节因子家族酶（Sirtuins enzymes）与细胞衰老及衰老进程密切相关。沉默信息调节因子蛋白的调控过程受到严格管控，但衰老过程中沉默信息调节因子的水平如何被调控，以及它们如何引发组织特异性的细胞变化，目前仍不明确。本研究证实，SIRT7在细胞衰老过程中会被靶向降解，且其表达受E3泛素连接酶TRIP12（E3 Ligase TRIP12）调控。研究发现，转录因子NUCKS1（transcription factor NUCKS1）可与SIRT7相互作用，并在细胞衰老过程中被招募至染色质上。该过程由SIRT7的缺失以及随后NUCKS1乙酰化水平的升高所介导。敲低NUCKS1可延缓细胞衰老，降低与RELA及CEBPβ相关的炎症基因表达水平。在Sirt7基因敲除（KO）小鼠及衰老肝脏组织中，NUCKS1结合于衰老相关基因的启动子和增强子区域，且这些区域在衰老过程中染色质可及性（chromatin accessibility）显著升高。综上，本研究结果揭示NUCKS1是SIRT7的相互作用蛋白；细胞衰老及肝脏衰老过程中SIRT7的蛋白酶体降解，会促进NUCKS1的乙酰化及染色质结合，从而诱导代谢相关基因与炎症基因的表达。