Deficiency of ATF2 retards senescence induced by replication stress and pamidronate in mouse jaw bone marrow stem cells.

Abstract

The aging process is associated with a loss of bone mass and an accumulation of senescent cells, which is under epigenetic control. Morphological and molecular analysis revealed a notable reduction in bone mass and alveolar crest height in aged mice, accompanied by increased levels of senescent mouse jaw bone marrow stem cells (mJBMSCs). To investigate whether specific transcription factors are involved, assay for transposase-accessible chromatin with sequencing (ATAC-seq) was performed on mJBMSCs isolated from 2-, 4-, 8-, and 20-month-old mice. In 20-month-old mJBMSCs, increased chromatin accessibility was observed alongside elevated expression of activating transcription factor 2 (ATF2) in both cells and alveolar bone. Silencing Atf2 in mJBMSCs failed to reverse physiological aging, but delayed replication stress and pamidronate (PAM) induced senescence. The analysis of ATAC-seq and RNA sequencing indicated that the differentially expressed genes upregulated by PAM but downregulated by ATF2 deficiency were related to some key biological processes, including negative regulation of cell proliferation, inflammatory response, adipogenesis, and cellular senescence. The dual-luciferase assay was conducted to demonstrate that ATF2 enhances Cdkn2a transcription by binding to its promoter region. Our findings suggest significant chromatin alterations in aged mJBMSCs, positioning ATF2 as a potential target for combating externally induced senescence.