Journal Article

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

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

2020

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Adult / Age Factors / Alveolar Epithelial Cells - classification / Alveolar Epithelial Cells - metabolism / Alveolar Epithelial Cells - virology / Angiotensin-Converting Enzyme 2 - genetics / Angiotensin-Converting Enzyme 2 - metabolism / Child, Preschool / Chromatin / Chromosome Mapping / cis-regulatory elements / COVID-19 / COVID-19 - genetics / COVID-19 - metabolism / COVID-19 - virology / Developmental Biology / Gene Expression Profiling / gene regulation / Genes / Genetic aspects / Genetic Variation / Genetics and Genomics / Health aspects / Host Microbial Interactions - genetics / Host Microbial Interactions - physiology / human sequence variants / Humans / Infant, Newborn / lung / Lung - metabolism / Lung - virology / Membrane Transport Proteins - genetics / Membrane Transport Proteins - metabolism / Pandemics / Receptors, Virus - genetics / Receptors, Virus - metabolism / SARS-CoV-2 - genetics / SARS-CoV-2 - pathogenicity / single cell RNA/ATAC-seq / Single-Cell Analysis / Virus Internalization