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Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes.

  • Author(s): Wang, Allen;
  • Chiou, Joshua;
  • Poirion, Olivier B;
  • Buchanan, Justin;
  • Valdez, Michael J;
  • Verheyden, Jamie M;
  • Hou, Xiaomeng;
  • Kudtarkar, Parul;
  • Narendra, Sharvari;
  • Newsome, Jacklyn M;
  • Guo, Minzhe;
  • Faddah, Dina A;
  • Zhang, Kai;
  • Young, Randee E;
  • Barr, Justinn;
  • Sajti, Eniko;
  • Misra, Ravi;
  • Huyck, Heidie;
  • Rogers, Lisa;
  • Poole, Cory;
  • Whitsett, Jeffery A;
  • Pryhuber, Gloria;
  • Xu, Yan;
  • Gaulton, Kyle J;
  • Preissl, Sebastian;
  • Sun, Xin;
  • NHLBI LungMap Consortium
  • et al.
Abstract

Respiratory failure associated with COVID-19 has placed focus on the lungs. Here, we present single-nucleus accessible chromatin profiles of 90,980 nuclei and matched single-nucleus transcriptomes of 46,500 nuclei in non-diseased lungs 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.

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