Stress-induced and ATF7-dependent epigenetic change influences cellular senescence.

Cellular senescence plays an important role in aging and is induced by cyclin-dependent kinase (Cdk) inhibitors that accumulate following stresses during aging. However, the underlying mechanism remains elusive. Herein, we demonstrate that activating transcription factor 7 (ATF7), the stress-responsive recruiter of histone H3K9 di- and trimethyltransferases, functions in the accumulation of Cdk inhibitors. Atf7-deficient (Atf7^-/- ) mice have a shorter lifespan than wild-type (WT) mice. Levels of p16^Ink4a Cdk inhibitor mRNA increased with age more rapidly in Atf7^-/- mice than in WT animals. ATF7 binds to the p16^Ink4a gene promoter and was released with age. Consistently, histone H3K9me2 levels on the p16^Ink4a gene promoter were lower in Atf7^-/- mice than in WT animals. Similar results were obtained when Atf7^-/- and WT mouse embryonic fibroblasts (MEFs) were cultured under 20% oxygen conditions, which induces cellular senescence via oxidative stress. Phosphorylation of ATF7 by p38 was also increased with the passage of MEFs, consistent with previous observations that ATF7 phosphorylation by p38 induces its release from chromatin. These results indicate that stress-induced and ATF7-dependent epigenetic changes on p16^Ink4a genes play an important role in cellular senescence.

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