Abstract
SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These aging-associated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
Highlights
Sirtuins, mammalian homologs of the yeast longevity protein Sir2, are evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases (HDACs) involved in metabolic regulation and aging (Bishop and Guarente, 2007; Finkel et al, 2009; Herskovits and Guarente, 2013; Zhang et al, 2018)
We found that SIRT7 downregulation associated with human mesenchymal stem cell (hMSC) senescence accounts for detachment of lamina-associated domains (LADs) from the nuclear lamina, loss of heterochromatin, and de-repression of long interspersed element 1 (LINE1), events that activate the innate immune response through the cyclic GMP-AMP synthase-stimulator of interferon genes signaling
Successful ablation of SIRT7 protein was verified with Western blot (Fig. S1B) while karyotyping and genome-wide copy number variation (CNV) analyses demonstrated that the genomic integrity of SIRT7-deficient (SIRT7−/−) Human embryonic stem cell (hESC) remained intact (Fig. S1C and S1D)
Summary
Mammalian homologs of the yeast longevity protein Sir, are evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases (HDACs) involved in metabolic regulation and aging (Bishop and Guarente, 2007; Finkel et al, 2009; Herskovits and Guarente, 2013; Zhang et al, 2018). SIRT7 has been implicated in hepatic lipid metabolism, cardiovascular system homeostasis and adipogenesis (Yoshizawa et al, 2014; Araki et al, 2015; Cioffi et al, 2015). SIRT7 is known as a direct transcriptional repressor that regulates mitochondrial and cytosolic protein homeostasis (Barber et al, 2012; Shin et al, 2013; Mohrin et al, 2015). Despite many seminal advances furthering our understanding of SIRT7 biology, the identification of reversible SIRT7-mediated cellular aging processes remains a challenge for the field
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