- 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
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.