ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Si Wang, Boqiang Hu, Zhichao Ding, Yujiao Dang, Jun Wu, Di Li, Xiaoling Liu, Bailong Xiao, Weiqi Zhang, Ruotong Ren, Jinghui Lei, Huifang Hu, Chang Chen, Piu Chan, Dong Li, Jing Qu, Fuchou Tang, Guang Hui Liu

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at gene expression level. Here, we report that human mesenchymal stem cell (hMSC) aging is associated with dysfunction of double-membrane organelles and downregulation of transcription factor ATF6. CRISPR/Cas9-mediated inactivation of ATF6 in hMSCs, not in human embryonic stem cells and human adipocytes, results in premature cellular aging, characteristic of loss of endomembrane homeostasis. Transcriptomic analyses uncover cell type-specific constitutive and stress-induced ATF6-regulated genes implicated in various layers of organelles' homeostasis regulation. FOS was characterized as a constitutive ATF6 responsive gene, downregulation of which contributes to hMSC aging. Our study unravels the first ATF6-regulated gene expression network related to homeostatic regulation of membrane organelles, and provides novel mechanistic insights into aging-associated attrition of human stem cells.

Original languageEnglish (US)
Article number2
JournalCell Discovery
Volume4
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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    Wang, S., Hu, B., Ding, Z., Dang, Y., Wu, J., Li, D., Liu, X., Xiao, B., Zhang, W., Ren, R., Lei, J., Hu, H., Chen, C., Chan, P., Li, D., Qu, J., Tang, F., & Liu, G. H. (2018). ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell Discovery, 4(1), [2]. https://doi.org/10.1038/s41421-017-0003-0