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PreprintCited by 1SARS-CoV-2 and COVID-19 Researchinterferon and immune responsesEpigenetics and DNA Methylation

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UHRF1 restricts HCoV-229E infection through epigenetic silencing of the viral receptor APN

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Wang, Pengcheng, Wang, Ziqiao, Feng, Fei, Yin, Lisha, Zhang, Yuyuan, Gao, Zhichao, Chen, Jiannan, Zhang, Ping, Yuan, Shuiqiao, Ding, Qiang, Hong, Yue, Song, Yuanlin, Li, Chun, Zhao, Jincun, Zhang, Rong·2025·Nature Communications
DOI 10.1101/2025.08.19.671085PMC PMC12627610

Preprint — published as 10.1038/s41467-025-64977-9

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Abstract

The emergence of SARS-CoV-2 has posed significant threats to global health, particularly for the older population. Similarly, common human coronaviruses, such as HCoV-229E, which typically cause mild cold-like symptoms, have also been linked to severe diseases, underscoring the need to understand virus-host interactions and identify host factors contributing to viral pathogenesis and disease progression. In this study, we performed a genome-wide CRISPR knockout screen using HCoV-229E and identified Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a potent restriction factor. Mechanistically, UHRF1 suppressed HCoV-229E infection by downregulating the expression of its cell entry receptor, aminopeptidase N (APN), through promoter hypermethylation. Focused CRISPR activation screens of UHRF1-downregulated genes confirmed the critical role of APN in HCoV-229E infection and identified additional genes (e.g., SIGLEC1, PLAC8, and heparan sulfate biosynthesis genes) contributing to the restrictive functions of UHRF1. Transcriptomic and single-cell RNA sequencing analysis revealed that UHRF1 expression decreases with age, negatively correlating with increased APN expression. This age-related decline in UHRF1 was further validated in primary alveolar macrophages isolated from elderly individuals, which exhibited heightened susceptibility to HCoV-229E infection compared to those from younger individuals. Our findings highlight UHRF1 as a key age-related host defense factor against coronavirus infection and provide novel insights into the epigenetic regulation of viral entry receptors.

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Metadata

Authors
Wang, P., Wang, Z., Feng, F., Yin, L., Zhang, Y., Gao, Z., Chen, J., Zhang, P., Yuan, S., Ding, Q., Hong, Y., Song, Y., Li, C., Zhao, J., & Zhang, R.
Affiliations
  • Shanghai Medical College of Fudan University (CN)
  • Huazhong University of Science and Technology (CN)
  • Sun Yat-sen University (CN)
  • Tsinghua University (CN)
  • Hainan University (CN)
  • Fudan University (CN)
  • First Affiliated Hospital of Guangzhou Medical University (CN)
Corresponding author
  • Li, Chun
  • Zhao, Jincun
  • Zhang, Rong
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2025-08-19
Volume
16
Issue
1
Pages
10085-10085
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2025.08.19.671085
PMC
PMC12627610
OpenAlex
W4416334304
Cited by
1
References
1
Citations by year
2026: 1
FWCI
0.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (ZD2021CY001, 82341084, 32041005)
  • Sun Yat-sen University
  • China Postdoctoral Science Foundation (2023M740658)
  • Fudan University (ZD2021CY001)
  • Ministry of Education, India
  • Chinese Academy of Medical Sciences (2023-PT310-02)
  • SENSHIN Medical Research Foundation
  • National Key Research and Development Program of China (2020YFA0707701, 2024YFC2607300)
  • Program of Shanghai Academic Research Leader (22XD1420600)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
UHRF1, HCoV-229E, human coronaviruses, APN, CD13, epigenetic silencing, promoter hypermethylation, DNA methylation, host restriction factors, viral entry receptor, alveolar macrophages, heparan sulfate biosynthesis, Siglec-1, PLAC8, CRISPR knockout screen, CRISPR activation screen, host-virus interaction
MeSH terms
COVID-19, Animals, Humans, Promoter Regions, Genetic, Receptors, Virus, Down-Regulation, Coronavirus Infections, DNA Methylation, Gene Silencing, CCAAT-Enhancer-Binding Proteins, Coronavirus 229E, Human, Epigenesis, Genetic, Ubiquitin-Protein Ligases, Host-Pathogen Interactions, HEK293 Cells

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