Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging

Zunpeng Liu¹, Qianzhao Ji², Jie Ren³, Pengze Yan², Zeming Wu², Si Wang⁴, Liang Sun⁵, Zehua Wang¹, Jiaming Li⁶, Guoqiang Sun¹, Chuqian Liang², Run Sun¹, Xiaoyu Jiang², Jianli Hu⁷, Yingjie Ding⁷, Qiaoran Wang⁶, Shijia Bi¹, Gang Wei⁸, Gang Cao⁹, Guoguang Zhao¹⁰, Hongmei Wang¹¹, Qi Zhou¹¹, Juan Carlos Izpisua Belmonte¹², Jing Qu¹³, Weiqi Zhang¹⁴, Guang-Hui Liu¹⁵

Affiliations

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
⁵ NHC Beijing Institute of Geriatrics, NHC Key Laboratory of Geriatrics, Institute of Geriatric Medicine of Chinese Academy of Medical Sciences, National Center of Gerontology/ Beijing Hospital, Beijing 100730, China; Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
⁶ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
⁷ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁸ CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Bio-Medical Center, Huazhong Agricultural University, Wuhan 430070, China.
¹⁰ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
¹¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
¹² Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, San Diego, CA 92037, USA.
¹³ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
¹⁴ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhangwq@big.ac.cn.
¹⁵ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 35613614
DOI: 10.1016/j.devcel.2022.05.004

Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging

Zunpeng Liu et al. Dev Cell. 2022.

. 2022 Jun 6;57(11):1347-1368.e12.

doi: 10.1016/j.devcel.2022.05.004. Epub 2022 May 24.

Authors

Affiliations

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
⁵ NHC Beijing Institute of Geriatrics, NHC Key Laboratory of Geriatrics, Institute of Geriatric Medicine of Chinese Academy of Medical Sciences, National Center of Gerontology/ Beijing Hospital, Beijing 100730, China; Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, China.
⁶ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
⁷ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁸ CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Bio-Medical Center, Huazhong Agricultural University, Wuhan 430070, China.
¹⁰ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
¹¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
¹² Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, San Diego, CA 92037, USA.
¹³ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
¹⁴ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhangwq@big.ac.cn.
¹⁵ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 35613614
DOI: 10.1016/j.devcel.2022.05.004

Abstract

Nuclear deformation, a hallmark frequently observed in senescent cells, is presumed to be associated with the erosion of chromatin organization at the nuclear periphery. However, how such gradual changes in higher-order genome organization impinge on local epigenetic modifications to drive cellular mechanisms of aging has remained enigmatic. Here, through large-scale epigenomic analyses of isogenic young, senescent, and progeroid human mesenchymal progenitor cells (hMPCs), we delineate a hierarchy of integrated structural state changes that manifest as heterochromatin loss in repressive compartments, euchromatin weakening in active compartments, switching in interfacing topological compartments, and increasing epigenetic entropy. We found that the epigenetic de-repression unlocks the expression of pregnancy-specific beta-1 glycoprotein (PSG) genes that exacerbate hMPC aging and serve as potential aging biomarkers. Our analyses provide a rich resource for uncovering the principles of epigenomic landscape organization and its changes in cellular aging and for identifying aging drivers and intervention targets with a genome-topology-based mechanism.

Keywords: 3D genome; aging biomarker; chromomatin entropy; epigenome; placenta-specific genes; pregnancy-specific beta-1 glycoprotein (PSG); progeria; senesence; stem cell aging.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging

Affiliations

Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances