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

Elife. 2020 Nov 9;9:e62522. doi: 10.7554/eLife.62522.

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.

Keywords: COVID-19; cis-regulatory elements; developmental biology; gene regulation; genetics; genomics; human; human sequence variants; lung; single cell RNA/ATAC-seq.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • COVID-19 / genetics*
  • COVID-19 / metabolism
  • COVID-19 / virology*
  • Child, Preschool
  • Chromosome Mapping
  • Gene Expression Profiling
  • Genetic Variation
  • Host Microbial Interactions / genetics*
  • Host Microbial Interactions / physiology
  • Humans
  • Infant, Newborn
  • 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 Analysis
  • Virus Internalization

Substances

  • Membrane Transport Proteins
  • Receptors, Virus
  • SLC6A20 protein, human
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Associated data

  • GEO/GSE161383