@article{27b9eda3915b47d7bee49c1fdb7e7110,
title = "Altered and allele-specific open chromatin landscape reveals epigenetic and genetic regulators of innate immunity in COVID-19",
abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe COVID-19 in some patients and mild COVID-19 in others. Dysfunctional innate immune responses have been identified to contribute to COVID-19 severity, but the key regulators are still unknown. Here, we present an integrative single-cell multi-omics analysis of peripheral blood mononuclear cells from hospitalized and convalescent COVID-19 patients. In classical monocytes, we identified genes that were potentially regulated by differential chromatin accessibility. Then, sub-clustering and motif-enrichment analyses revealed disease condition-specific regulation by transcription factors and their targets, including an interaction between C/EBPs and a long-noncoding RNA LUCAT1, which we validated through loss-of-function experiments. Finally, we investigated genetic risk variants that exhibit allele-specific open chromatin (ASoC) in COVID-19 patients and identified a SNP rs6800484-C, which is associated with lower expression of CCR2 and may contribute to higher viral loads and higher risk of COVID-19 hospitalization. Altogether, our study highlights the diverse genetic and epigenetic regulators that contribute to COVID-19.",
keywords = "allele-specific open chromatin, COVID-19, epigenetic regulation, genetic regulation, scATAC-seq, scRNA-seq",
author = "Bowen Zhang and Zhenhua Zhang and Koeken, {Valerie A.C.M.} and Saumya Kumar and Michelle Aillaud and Tsay, {Hsin Chieh} and Zhaoli Liu and Kraft, {Anke R.M.} and Soon, {Chai Fen} and Ivan Odak and Berislav Bo{\v s}njak and Anna Vlot and Swertz, {Morris A.} and Uwe Ohler and Robert Geffers and Thomas Illig and Jochen Huehn and Saliba, {Antoine Emmanuel} and Sander, {Leif Erik} and Reinhold F{\"o}rster and Xu, {Cheng Jian} and Markus Cornberg and Schulte, {Leon N.} and Yang Li",
note = "Funding Information: The authors thank all volunteers from the Hannover Medical School (MHH) for participation in the study. This study was supported by the COFONI (COVID-19 Research Network of the State of Lower Saxony) with funding from the Ministry of Science and Culture of Lower Saxony, Germany (14-76403-184) to Y.L. R.F. T.I. and J.H.; the Network Universities of Medicine (NUM) CODEX+ fund from the Federal Ministry of Education and Research (BMBF) to Y.L.; the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany's Excellence Strategy—EXC 2155 project number 390874280 to Y.L.; and the Helmholtz Centre for Infection Research network fund (NASAVIR) to Y.L. and J.H. Y.L. was also supported by a European Research Council (ERC) Starting Grant (948207) and the Radboud University Medical Center Hypatia Grant (2018) for Scientific Research. Z.Z. was supported by a joint scholarship by the University of Groningen and China Scholarship Consortium (CSC201706350277) and Singh-Chhatwal-Postdoctoral Fellowship at the Helmholtz Centre for Infection Research. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on May 28, 2021. A.-E.S. acknowledges FOR-COVID (Bayerisches Staatsministerium f{\"u}r Wissenschaft und Kunst) and the Helmholtz Association for support. Conceptualization and study design: Y.L.; data analysis and investigation: B.Z. Z.Z. V.A.C.M.K. S.K. A.V. and R.G.; loss-of-function experiments: L.N.S.; discussion and interpretation: B.Z. Z.Z. V.A.C.M.K. Y.L. C.-J.X. S.K. M.C. L.N.S. L.E.S. A.V. U.O. and J.H.; sample collection and biospecimen resources: M.C. L.N.S. R.F. T.I. U.O. H.-C.T. Z.L. C.F.S. B.B. and R.G.; writing – original manuscript: B.Z. Z.Z. and V.A.C.M.K.; review and editing manuscript: all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: The authors thank all volunteers from the Hannover Medical School (MHH) for participation in the study. This study was supported by the COFONI (COVID-19 Research Network of the State of Lower Saxony) with funding from the Ministry of Science and Culture of Lower Saxony, Germany ( 14-76403-184 ) to Y.L., R.F., T.I., and J.H.; the Network Universities of Medicine (NUM) CODEX+ fund from the Federal Ministry of Education and Research (BMBF) to Y.L.; the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany{\textquoteright}s Excellence Strategy—EXC 2155 project number 390874280 to Y.L.; and the Helmholtz Centre for Infection Research network fund (NASAVIR) to Y.L. and J.H. Y.L. was also supported by a European Research Council (ERC) Starting Grant ( 948207 ) and the Radboud University Medical Center Hypatia Grant ( 2018 ) for Scientific Research. Z.Z. was supported by a joint scholarship by the University of Groningen and China Scholarship Consortium ( CSC201706350277 ) and Singh-Chhatwal-Postdoctoral Fellowship at the Helmholtz Centre for Infection Research. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute ( NCI ), National Human Genome Research Institute ( NHGRI ), National Heart, Lung, and Blood Institute ( NHLBI ), National Institute on Drug Abuse ( NIDA ), National Institute of Mental Health ( NIMH ), and National Institute of Neurological Disorders and Stroke ( NINDS ). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on May 28, 2021. A.-E.S. acknowledges FOR-COVID (Bayerisches Staatsministerium f{\"u}r Wissenschaft und Kunst) and the Helmholtz Association for support. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2023",
month = feb,
doi = "10.1016/j.xgen.2022.100232",
language = "English",
volume = "3",
journal = "Cell Genomics",
issn = "2666-979X",
publisher = "Cell Press",
number = "2",
}