Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging.

Yiyuan Zhang; Yandong Zheng; Si Wang; Yanling Fan; Yanxia YE; Yaobin Jing; Zunpeng Liu; Shanshan Yang; Muzhao Xiong; Kuan Yang; Jinghao HU; Shanshan Che; Qun Chu; Moshi Song; Guang-hui Liu; Weiqi Zhang; Shuai MA; Jing QU

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Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging.

Author: Yiyuan ZHANG ¹ ; Yandong ZHENG ² ; Si WANG ³ ; Yanling FAN ⁴ ; Yanxia YE ² ; Yaobin JING ⁵ ; Zunpeng LIU ² ; Shanshan YANG ³ ; Muzhao XIONG ⁶ ; Kuan YANG ⁶ ; Jinghao HU ³ ; Shanshan CHE ⁶ ; Qun CHU ² ; Moshi SONG ⁵ ; Guang-Hui LIU ¹ ; Weiqi ZHANG ⁶ ; Shuai MA ⁵ ; Jing QU ²
Author Information

1. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
2. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
3. Aging Translational Medicine Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
4. CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
5. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
6. University of Chinese Academy of Sciences, Beijing 100049, China.
Publication Type:Research Support, Non-U.S. Gov't
Keywords: FOXP1; aging; cardiomyocyte; primate; single-nucleus RNA-sequencing
MeSH: Aged; Animals; Humans; Aging/genetics*; Forkhead Transcription Factors/metabolism*; Myocytes, Cardiac/metabolism*; Primates/metabolism*; Repressor Proteins/metabolism*; Transcriptome; Macaca fascicularis/metabolism*
From: Protein & Cell 2023;14(4):279-293
CountryChina
Language:English
Abstract: Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.