Altered and allele-specific open chromatin landscape reveals epigenetic and genetic regulators of innate immunity in COVID-19
Authors/Creators
- Zhang, Bowen1
- Zhang, Zhenhua1
- Koeken, Valerie A. C. M.1
- Kumar, Saumya1
- Aillaud, Michelle
- Tsay, Hsin-Chieh
- Liu, Zhaoli1
- Kraft, Ane R. M.
- Soon, Chai Fen
- Odak, Ivan
- Bosnjak, Berislay
- Volt, Anna
- Deutsche COVID-19 OMICS Initiative (DeCOI)
- Swertz, Morris A.
- Ohler, Uwe
- Geffers, Robert
- Illig, Thomas
- Huehn, Jochen
- Saliba, Antoine-Emmanuel
- Sander, Leif Erik
- Förster, Reinhold
- Xu, Cheng-Jian1
- Cornberg, Markus
- Schulte, Leon N.
- Li, Yang1
- 1. Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
Description
While SARS-CoV-2 infection causes mild respiratory disease in most individuals, a small group of patients develops severe COVID-19. Dysfunctional innate immune responses have been identified to contribute to differences in COVID-19 severity, but the key regulators are still unknown. Here, we present an integrative single-cell epigenetics, transcriptomic, and genetics analysis of peripheral blood mononuclear cells from hospitalized and convalescent COVID-19 patients. In classical monocytes, we identified 41.3% of significantly up-regulated genes in hospitalized COVID-19 patients potentially induced by differential chromatin accessibility. Sub-clustering and motif-enrichment analyses of monocytes reveal disease condition-specific regulation by transcription factors, such as C/EBPs and SPI1, and their targets, including a long-noncoding RNA LUCAT1, which further regulates interferon responses and is associated with the need for oxygen supply of COVID-19 patients. The interaction between C/EBPs and LUCAT1 was validated through loss-of-function experiments. Finally, we investigated genetic risk variants that exhibit allele-specific open chromatin (ASoC) in promoters/enhancers of COVID-19 patients. Integrating our data with publicly available expression quantitative trait loci and chromosomal interactions indicates that ASoC SNP rs6800484-C is associated with lower expression of CCR2, which may contribute to higher viral loads in the lungs and a higher risk of COVID-19 hospitalization. Altogether, our study highlights the diverse genetic and epigenetic regulators that contribute to the innate immune responses of different COVID-19 patients.
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