1. Developmental Biology
  2. Genetics and Genomics
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Single cell multiomic profiling of human lung reveals cell type-specific and age-dynamic control of SARS-CoV2 host genes

  1. Allen Wang  Is a corresponding author
  2. Joshua Chiou
  3. Olivier B Poirion
  4. Justin Buchanan
  5. Michael J Valdez
  6. Jamie M Verheyden
  7. Xiaomeng Hou
  8. Parul Kudtarkar
  9. Sharvari Narendra
  10. Jacklyn M Newsome
  11. Minzhe Guo
  12. Dina A Faddah
  13. Kai Zhang
  14. Randee E Young
  15. Justinn Barr
  16. Eniko Sajti
  17. Ravi Misra
  18. Heidie Huyck
  19. Lisa Rogers
  20. Cory Poole
  21. Jeffery A Whitsett
  22. Gloria Pryhuber
  23. Yan Xu
  24. Kyle J Gaulton  Is a corresponding author
  25. Sebastian Preissl  Is a corresponding author
  26. Xin Sun  Is a corresponding author
  27. NHLBI LungMap Consortium
  1. University of California, San Diego, United States
  2. Cincinnati Children's Hospital Medical Center/University of Cincinnati College of Medicine, United States
  3. Vertex Pharmaceuticals, United States
  4. Ludwig Institute for Cancer Research, United States
  5. University of Rochester Medical Center, United States
  6. Cincinnati Children's Hospital Medical Center, United States
  7. CCHMC/University of Cincinnati, United States
Research Article
  • Cited 26
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Cite this article as: eLife 2020;9:e62522 doi: 10.7554/eLife.62522

Abstract

Respiratory failure associated with COVID-19 has placed focus on the lung. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lung from donors of ~30 weeks gestation, ~3 years and ~30 years. We mapped candidate cis-regulatory elements (cCREs) and linked them to putative target genes. We identified distal cCREs with age-increased activity linked to SARS-CoV-2 host entry gene TMPRSS2 in alveolar type 2 cells which had immune regulatory signatures and harbored variants associated with respiratory traits. At the 3p21.31 COVID-19 risk locus, a candidate variant overlapped a distal cCRE linked to SLC6A20, a gene expressed in alveolar cells and with known functional association with the SARS-CoV-2 receptor ACE2. Our findings provide insight into regulatory logic underlying genes implicated in COVID-19 in individual lung cell types across age. More broadly, these datasets will facilitate interpretation of risk loci for lung diseases.

Data availability

Processed data including the full list of peaks are available for download and can be explored using the web portal www.lungepigenome.org. Raw sequencing files has been submitted to LungMap Data Collecting Core and will be submitted to dbGAP.Source data for Figure 1 - figure supplement 1 is available as Supplementary Table 2; Source data for Figure 3B and Figure 3 - figure supplement 1A is available as Supplementary Table 3. Source data for Figure 3E is available as Supplementary Table 4. Source data for Figure 3F is available as Supplementary Table 5. Source data for Figure 3G is available as Supplementary Table 6.Source data for Figure 4A is available as Supplementary Table 7.

Article and author information

Author details

  1. Allen Wang

    Department of Pediatrics and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    For correspondence
    a5wang@ucsd.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9870-7888
  2. Joshua Chiou

    Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4618-0647
  3. Olivier B Poirion

    Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  4. Justin Buchanan

    Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  5. Michael J Valdez

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  6. Jamie M Verheyden

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  7. Xiaomeng Hou

    Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. Parul Kudtarkar

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  9. Sharvari Narendra

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  10. Jacklyn M Newsome

    Department of Pediatrics, Rady Children's Hospital, Division of Genome Information Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  11. Minzhe Guo

    Division of Neonatology, Perinatal and Pulmonary/Divisions of Pulmonary Biology and Biomedical Informatics Biology/, Cincinnati Children's Hospital Medical Center/University of Cincinnati College of Medicine, Cincinnati, United States
    Competing interests
    No competing interests declared.
  12. Dina A Faddah

    Vertex Pharmaceuticals, Vertex Pharmaceuticals, San Diego, United States
    Competing interests
    No competing interests declared.
  13. Kai Zhang

    Ludwig Institute for Cancer Research, La Jolla, United States
    Competing interests
    No competing interests declared.
  14. Randee E Young

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  15. Justinn Barr

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  16. Eniko Sajti

    Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  17. Ravi Misra

    Pediatrics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    No competing interests declared.
  18. Heidie Huyck

    Pediatrics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    No competing interests declared.
  19. Lisa Rogers

    Pediatrics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    No competing interests declared.
  20. Cory Poole

    Pediatrics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    No competing interests declared.
  21. Jeffery A Whitsett

    Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    No competing interests declared.
  22. Gloria Pryhuber

    Pediatrics, University of Rochester Medical Center, Rochester, United States
    Competing interests
    No competing interests declared.
  23. Yan Xu

    Division of Neonatology, Perinatal and Pulmonary/Divisions of Pulmonary Biology and Biomedical Informatics Biology, CCHMC/University of Cincinnati, Cincinnati, United States
    Competing interests
    No competing interests declared.
  24. Kyle J Gaulton

    Department of Pediatrics, University of California, San Diego, La Jolla, United States
    For correspondence
    kgaulton@health.ucsd.edu
    Competing interests
    Kyle J Gaulton, KJG does consulting for Genentech, DAF is an employee and holds stock in Vertex Pharmaceuticals.
  25. Sebastian Preissl

    Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    For correspondence
    spreissl@health.ucsd.edu
    Competing interests
    No competing interests declared.
  26. Xin Sun

    Pediatrics, University of California, San Diego, La Jolla, United States
    For correspondence
    xinsun@health.ucsd.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8387-4966
  27. NHLBI LungMap Consortium

Funding

National Heart, Lung, and Blood Institute (1U01HL148867)

  • Allen Wang
  • Jamie M Verheyden
  • Sebastian Preissl
  • Xin Sun

National Heart, Lung, and Blood Institute (U01HL122700)

  • Gloria Pryhuber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Publication history

  1. Received: August 27, 2020
  2. Accepted: November 8, 2020
  3. Accepted Manuscript published: November 9, 2020 (version 1)
  4. Version of Record published: November 25, 2020 (version 2)

Copyright

© 2020, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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