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

iScience (Nov 2019)

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

Affiliations

Biao Huang: 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
Bin Wang: 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
Wayne Yuk-Wai Lee: 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
Kin Pong U: 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
Kam Tong Leung: Department of Pediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China
Xican Li: 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
Zhenqing Liu: 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
Rui Chen: 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
Jia cheng Lin: 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
Lai Ling Tsang: 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
Baohua Liu: Shenzhen University Health Science Center, Shenzhen University, Shenzhen, PR China
Ye chun Ruan: Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, PR China
Hsiao Chang Chan: 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
Gang Li: 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
Xiaohua Jiang: 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; Corresponding author

Journal volume & issue: Vol. 21
pp. 375 – 390

Abstract

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

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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