N6-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

doi:10.1007/s11427-024-2793-x

. 2025 Aug;68(8):2456-2471.

doi: 10.1007/s11427-024-2793-x. Epub 2025 May 30.

N⁶-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

Yaxu Liang^#¹, Weiwei Yu^#², Haifeng Sun^#³, Dayu Wang¹, Zhibo Wang¹, Hailing Shi^{4

5

6}, Yang Cao⁴, Zijie Zhang^{4

7}, Jun Liu^{4

8}, Zhongyu Zou⁴, Jiangbo Wei⁴, Tong Wu⁴, Dongming Yu¹, Jun Qi¹, Jiamin Wu¹, Bryan C Dickinson⁴, Pingping Zhu⁹, Bin Shen¹⁰, Beicheng Sun¹¹, Chuan He^{4

5

6}, Xiang Zhong^{12

13}

Affiliations

¹ College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
² Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China.
³ State Key Laboratory of Reproductive Medicine and Offspring Health, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Center for Global Health, Gusu School, Nanjing Medical University, Nanjing, 211166, China.
⁴ Department of Chemistry, University of Chicago, Chicago, 60637, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, 60637, USA.
⁶ Howard Hughes Medical Institute, University of Chicago, Chicago, 60637, USA.
⁷ State Key Laboratory for Conservation and Utilization of Bio-resources and School of Life Sciences, Yunnan University, Kunming, 650091, China.
⁸ State Key Laboratory of Protein and Plant Gene Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, 100871, China.
⁹ School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
¹⁰ State Key Laboratory of Reproductive Medicine and Offspring Health, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Center for Global Health, Gusu School, Nanjing Medical University, Nanjing, 211166, China. binshen@njmu.edu.cn.
¹¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. sunbc@ahmu.edu.cn.
¹² College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China. zhongxiang@njau.edu.cn.
¹³ Natural Plant and Animal Health Innovation Institute, NJAU-Cohoo Biotechnology, Nanjing Agricultural University, Nanjing, 210095, China. zhongxiang@njau.edu.cn.

^# Contributed equally.

PMID: 40488955
DOI: 10.1007/s11427-024-2793-x

N⁶-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

Yaxu Liang et al. Sci China Life Sci. 2025 Aug.

. 2025 Aug;68(8):2456-2471.

doi: 10.1007/s11427-024-2793-x. Epub 2025 May 30.

Authors

Affiliations

¹ College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
² Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210093, China.
³ State Key Laboratory of Reproductive Medicine and Offspring Health, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Center for Global Health, Gusu School, Nanjing Medical University, Nanjing, 211166, China.
⁴ Department of Chemistry, University of Chicago, Chicago, 60637, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, 60637, USA.
⁶ Howard Hughes Medical Institute, University of Chicago, Chicago, 60637, USA.
⁷ State Key Laboratory for Conservation and Utilization of Bio-resources and School of Life Sciences, Yunnan University, Kunming, 650091, China.
⁸ State Key Laboratory of Protein and Plant Gene Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, 100871, China.
⁹ School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
¹⁰ State Key Laboratory of Reproductive Medicine and Offspring Health, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Center for Global Health, Gusu School, Nanjing Medical University, Nanjing, 211166, China. binshen@njmu.edu.cn.
¹¹ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China. sunbc@ahmu.edu.cn.
¹² College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China. zhongxiang@njau.edu.cn.
¹³ Natural Plant and Animal Health Innovation Institute, NJAU-Cohoo Biotechnology, Nanjing Agricultural University, Nanjing, 210095, China. zhongxiang@njau.edu.cn.

^# Contributed equally.

PMID: 40488955
DOI: 10.1007/s11427-024-2793-x

Abstract

Liver injury is a major health issue with significant implications for liver function and overall well-being, but precise mechanisms of the N⁶-methyladenine (m⁶A) reader YTHDF3 in liver injury remain severely understudied. Here, we discovered that Ythdf3 knockout exacerbated CCL₄-induced liver injury with a reduction in functional hepatocytes and liver stem cells using single cell RNA-sequencing and organoid culture. Furthermore, Mettl14 and YTHDF3-dependent RNA m⁶A dysregulation induced DNA damage. Moreover, we found YTHDF3 could bind and modulate CCAAT/enhancer-binding protein-alpha (CEBPA) translation in an m⁶A-dependent manner. Mechanistically, knockout of Ythdf3 impeded the translation of CEBPA, subsequently inhibiting the expression of poly(ADP-ribose) (PAR) polymerase-1 (PARP1) and Peroxiredoxin 2 (PRDX2). This inhibition promoted DNA damage and genomic instability, ultimately exacerbating liver damage. This work uncovers an essential role of m⁶A/YTHDF3/CEBPA regulatory axes in governing cell fates and genomic stability, thereby preventing liver injury. Importantly, these findings offer potential therapeutic avenues for targeting YTHDF3 and CEBPA in the treatment of liver injury-related diseases.

Keywords: CEBPA; YTHDF3; genome stability; liver injury; stem cell.

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Conflict of interest statement

Compliance and ethics. The authors declare that they have no conflict of interest. The procedures involving mice experiments were conducted in accordance with guidelines set by the Animal Ethics Committee of Nanjing Agricultural University (Permit number SYXK-2017-0007).

References

1. Avellino, R., Havermans, M., Erpelinck, C., Sanders, M.A., Hoogenboezem, R., van de Werken, H.J.G., Rombouts, E., van Lom, K., van Strien, P.M.H., Gebhard, C., et al. (2016). An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. Blood 127, 2991–3003.
1. Bai, P. (2015). Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol Cell 58, 947–958.
1. Batista, P.J., Molinie, B., Wang, J., Qu, K., Zhang, J., Li, L., Bouley, D.M., Lujan, E., Haddad, B., Daneshvar, K., et al. (2014). m⁶A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719.
1. Bhaskara, S., Knutson, S.K., Jiang, G., Chandrasekharan, M.B., Wilson, A.J., Zheng, S., Yenamandra, A., Locke, K., Yuan, J., Bonine-Summers, A.R., et al. (2010). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436–447.
1. Chelmicki, T., Roger, E., Teissandier, A., Dura, M., Bonneville, L., Rucli, S., Dossin, F., Fouassier, C., Lameiras, S., and Bourc’his, D. (2021). m⁶A RNA methylation regulates the fate of endogenous retroviruses. Nature 591, 312–316.

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[1] Avellino, R., Havermans, M., Erpelinck, C., Sanders, M.A., Hoogenboezem, R., van de Werken, H.J.G., Rombouts, E., van Lom, K., van Strien, P.M.H., Gebhard, C., et al. (2016). An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. Blood 127, 2991–3003.

[2] Avellino, R., Havermans, M., Erpelinck, C., Sanders, M.A., Hoogenboezem, R., van de Werken, H.J.G., Rombouts, E., van Lom, K., van Strien, P.M.H., Gebhard, C., et al. (2016). An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. Blood 127, 2991–3003.

[3] Bai, P. (2015). Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol Cell 58, 947–958.

[4] Bai, P. (2015). Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol Cell 58, 947–958.

[5] Batista, P.J., Molinie, B., Wang, J., Qu, K., Zhang, J., Li, L., Bouley, D.M., Lujan, E., Haddad, B., Daneshvar, K., et al. (2014). m⁶A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719.

[6] Batista, P.J., Molinie, B., Wang, J., Qu, K., Zhang, J., Li, L., Bouley, D.M., Lujan, E., Haddad, B., Daneshvar, K., et al. (2014). m⁶A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719.

[7] Bhaskara, S., Knutson, S.K., Jiang, G., Chandrasekharan, M.B., Wilson, A.J., Zheng, S., Yenamandra, A., Locke, K., Yuan, J., Bonine-Summers, A.R., et al. (2010). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436–447.

[8] Bhaskara, S., Knutson, S.K., Jiang, G., Chandrasekharan, M.B., Wilson, A.J., Zheng, S., Yenamandra, A., Locke, K., Yuan, J., Bonine-Summers, A.R., et al. (2010). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18, 436–447.

[9] Chelmicki, T., Roger, E., Teissandier, A., Dura, M., Bonneville, L., Rucli, S., Dossin, F., Fouassier, C., Lameiras, S., and Bourc’his, D. (2021). m⁶A RNA methylation regulates the fate of endogenous retroviruses. Nature 591, 312–316.

[10] Chelmicki, T., Roger, E., Teissandier, A., Dura, M., Bonneville, L., Rucli, S., Dossin, F., Fouassier, C., Lameiras, S., and Bourc’his, D. (2021). m⁶A RNA methylation regulates the fate of endogenous retroviruses. Nature 591, 312–316.

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N⁶-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

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N⁶-methyladenosine reader YTHDF3-mediated CEBPA translation maintains genomic stability and stem cell function to prevent liver injury

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