Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

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

doi:10.1101/2020.04.12.037580

GenomicsbioRxivApr 12, 2020

Preprint

Single Nucleus Multiomic Profiling Reveals Age-Dynamic Regulation of Host Genes Associated with SARS-CoV-2 Infection

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

Abstract

Respiratory failure is the leading cause of COVID-19 death and disproportionately impacts adults more than children. Here, we present a large-scale snATAC-seq dataset (90,980 nuclei) of the human lung, generated in parallel with snRNA-seq (46,500 nuclei), from healthy donors of ~30 weeks, ~3 years and ~30 years of age. Focusing on genes implicated in SARS-CoV-2 cell entry, we observed an increase in the proportion of alveolar epithelial cells expressing ACE2 and TMPRSS2 in adult compared to young lungs. Consistent with expression dynamics, 10 chromatin peaks linked to TMPRSS2 exhibited significantly increased activity with age and harbored IRF and STAT binding sites. Furthermore, we identified 14 common sequence variants in age-increasing peaks with predicted regulatory function, including several associated with respiratory traits and TMPRSS2 expression. Our findings reveal a plausible contributor to why children are more resistant to COVID-19 and provide an epigenomic basis for transferring this resistance to older populations.

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