KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization

Biao Huang; Bin Wang; Wayne Yuk-Wai Lee; Kin Pong U; Kam Tong Leung; Xican Li; Zhenqing Liu; Rui Chen; Jia Cheng Lin; Lai Ling Tsang; Baohua Liu; Ye Chun Ruan; Hsiao Chang Chan; Gang Li; Xiaohua Jiang

doi:10.1016/j.isci.2019.10.041

KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization

iScience. 2019 Nov 22:21:375-390. doi: 10.1016/j.isci.2019.10.041. Epub 2019 Oct 24.

Authors

Biao Huang¹, Bin Wang², Wayne Yuk-Wai Lee², Kin Pong U¹, Kam Tong Leung³, Xican Li⁴, Zhenqing Liu⁵, Rui Chen⁵, Jia Cheng Lin¹, Lai Ling Tsang¹, Baohua Liu⁶, Ye Chun Ruan⁷, Hsiao Chang Chan¹, Gang Li², Xiaohua Jiang⁸

Affiliations

¹ Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Room 409A, Lo Kwee Seong Integrated Biomedical Sciences Building, Area 39, Shatin, Hong Kong SAR, PR China; The Chinese University of Hong Kong, Shenzhen Research Institute, Shenzhen, PR China.
² The Chinese University of Hong Kong, Shenzhen Research Institute, Shenzhen, PR China; Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
³ Department of Pediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
⁴ School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China; Innovative Research & Development Laboratory of TCM, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
⁵ Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Room 409A, Lo Kwee Seong Integrated Biomedical Sciences Building, Area 39, Shatin, Hong Kong SAR, PR China.
⁶ Shenzhen University Health Science Center, Shenzhen University, Shenzhen, PR China.
⁷ Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, PR China.
⁸ Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Room 409A, Lo Kwee Seong Integrated Biomedical Sciences Building, Area 39, Shatin, Hong Kong SAR, PR China; The Chinese University of Hong Kong, Shenzhen Research Institute, Shenzhen, PR China. Electronic address: xjiang@cuhk.edu.hk.

Abstract

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.

Keywords: Cell Biology; DNA damage; Molecular Mechanism of Gene Regulation; Stem Cells Research; bone aging; condensin; epigenetic regulation; histone demethylase; mesenchymal stromal cells.