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

Allen Wang; Joshua A Chiou; Olivier B 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 Misra; Heidie Huyck; Lisa Rogers; Cory Poole; Jeffery A Whitsett; Gloria Pryhuber; Yan Xu; Kyle J Gaulton; Sebastian Preissl; Xin Sun

We identified two clusters of AT2 sites exhibiting increasing accessibility with age 365 including several sites at candidate genes for SARS-CoV-2 host genes (cIII 30yo enriched 366 and cIV 3yo + 30yo) ( Figure 3B , Figure S6A We focused on the TMPRSS2 locus and determined how many of the 37 accessible 378 chromatin sites co-accessible with the TMPRSS2 promoter (in Figure 2D ) showed 379 increased accessibility with age in AT2 cells. We identified 13 sites with age-increased 380 accessibility, of which 10 had significant effects (FDR < 0.05 via EdgeR and/or p < 0.05 381 via t-test) ( Figure 3E , F, Figure S6 , Supplementary CEBPA, and inflammation-related factors such as STAT, IRF, and FOS/JUN ( Figure 3G ) 384 many of which were corroborated by available ChIP-seq data in lung related samples (Oki 385 et al., 2018) . Furthermore, at 12 of the 13 age-increasing sites, we uncovered additional 386 evidence for enhancer-related histone modifications from ENCODE supporting that they 387 have cis-regulatory activity ( Figure 3H ) (Consortium, 2012) . When viewed in genomic 388 context these sites showed a clear age-dependent increase in read depth likely reflecting 389 a higher fraction of accessible nuclei ( Figure 3I ). 390 391 Genetic variants predicted to affect age-increased TMPRSS2 sites are associated 392 with respiratory phenotypes and TMPRSS2 expression 393