Epigenomic changes and stem cell deterioration are two hallmarks of aging. Accumulating evidence suggest that senescence of mesenchymal stromal cells (MSCs) perpetuates aging or age-related diseases. Here we report that two H3K9 demethylases, KDM3A and KDM4C, regulate heterochromatin reorganization via transcriptionally activating condensin components NCAPD2 and NCAPG2 during MSC senescence. Suppression of KDM3A or KDM4C by either genetic or biochemical approach leads to robust DNA damage response and aggravates cellular senescence, whereas overexpression of KDM3A/KDM4C or NCAPD2 promotes heterochromatin reorganization and blunts DNA damage response. Moreover, MSCs derived from Kdm3a−/− mice exhibit defective chromosome organization and exacerbated DNA damage response, which are associated with accelerated bone aging. Consistently, analysis of human bone marrow MSCs and transcriptome database reveals inverse correlation of KDM3A/KDM4C and/or NCAPD2/NCAPG2 with aging. Taken together, the present finding unveils that H3K9 demethylases function as a surveillance mechanism to restrain DNA damage accumulation in stem cells during aging.

表观基因组变化和干细胞退化是衰老的两个标志。越来越多的证据表明，间质基质细胞（MSC）的衰老使衰老或与年龄有关的疾病永存。在这里我们报告说，两个H3K9脱甲基酶KDM3A和KDM4C通过在MSC衰老过程中通过转录激活凝缩蛋白成分NCAPD2和NCAPG2来调节异染色质的重组。通过遗传或生化方法抑制KDM3A或KDM4C会导致强大的DNA损伤反应并加剧细胞衰老，而KDM3A / KDM4C或NCAPD2的过表达促进异染色质重组并钝化DNA损伤反应。此外，从Kdm3a -/-小鼠表现出缺陷的染色体组织和加剧的DNA损伤反应，这与骨老化加速有关。一致地，对人骨髓MSC和转录组数据库的分析揭示了KDM3A / KDM4C和/或NCAPD2 / NCAPG2与衰老呈负相关。综上所述，本发明发现揭示了H3K9脱甲基酶充当监视机制，以抑制衰老过程中干细胞中DNA损伤的积累。