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

Research output: Journal article publicationJournal articleAcademic researchpeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)375-390
Number of pages16
JournaliScience
Volume21
DOIs
Publication statusPublished - 22 Nov 2019

Keywords

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

ASJC Scopus subject areas

  • General

Cite this