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

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: Contribution to journal › Article › peer-review

41 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 language	English
Pages (from-to)	375-390
Number of pages	16
Journal	iScience
Volume	21
DOIs	https://doi.org/10.1016/j.isci.2019.10.041
Publication status	Published - 22 Nov 2019
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2019.10.041

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Huang, B., Wang, B., Yuk-Wai Lee, W., Pong U, K., Leung, K. T., Li, X., Liu, Z., Chen, R., Lin, J. C., Tsang, L. L., Liu, B., Ruan, Y. C., Chan, H. C., Li, G., & Jiang, X. (2019). KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization. iScience, 21, 375-390. https://doi.org/10.1016/j.isci.2019.10.041

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

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",

author = "Biao Huang and Bin Wang and {Yuk-Wai Lee}, Wayne and {Pong U}, Kin and Leung, {Kam Tong} and Xican Li and Zhenqing Liu and Rui Chen and Lin, {Jia cheng} and Tsang, {Lai Ling} and Baohua Liu and Ruan, {Ye chun} and Chan, {Hsiao Chang} and Gang Li and Xiaohua Jiang",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = nov,

day = "22",

doi = "10.1016/j.isci.2019.10.041",

language = "English",

volume = "21",

pages = "375--390",

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TY - JOUR

T1 - KDM3A and KDM4C Regulate Mesenchymal Stromal Cell Senescence and Bone Aging via Condensin-mediated Heterochromatin Reorganization

AU - Huang, Biao

AU - Wang, Bin

AU - Yuk-Wai Lee, Wayne

AU - Pong U, Kin

AU - Leung, Kam Tong

AU - Li, Xican

AU - Liu, Zhenqing

AU - Chen, Rui

AU - Lin, Jia cheng

AU - Tsang, Lai Ling

AU - Liu, Baohua

AU - Ruan, Ye chun

AU - Chan, Hsiao Chang

AU - Li, Gang

AU - Jiang, Xiaohua

PY - 2019/11/22

Y1 - 2019/11/22

N2 - 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.

AB - 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.

KW - Cell Biology

KW - DNA damage

KW - Molecular Mechanism of Gene Regulation

KW - Stem Cells Research

KW - bone aging

KW - condensin

KW - epigenetic regulation

KW - histone demethylase

KW - mesenchymal stromal cells

UR - http://www.scopus.com/inward/record.url?scp=85074398829&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2019.10.041

DO - 10.1016/j.isci.2019.10.041

M3 - Article

AN - SCOPUS:85074398829

VL - 21

SP - 375

EP - 390

JO - iScience

JF - iScience

ER -

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

Abstract

Keywords

UN SDGs

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