rs2564978(T) allele associated with severe influenza a disrupts binding site for myeloid differentiation factor PU.1 and reduces CD55/DAF gene promoter activity in macrophages

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Abstract

An inhibitor of the complement system CD55/DAF is expressed on many cell types. Dysregulation of CD55 expression is associated with increased disease severity during influenza A infection, as well as with vascular complications in pathologies involving excessive activation of the complement system. Using a luciferase reporter system, we performed functional analysis of the single nucleotide polymorphism rs2564978 located in the promoter of the CD55 gene in human pro-monocytic cell line U937. We have shown a decreased activity in activated U937 cells of the CD55 gene promoter carrying minor rs2564978(T) allele associated with the severe course of influenza A(H1N1)pdm09. Using bioinformatic resources, we determined that transcription factor PU.1 can potentially bind to the CD55 promoter region containing rs2564978 in an allele-specific manner. The involvement of PU.1 in modulating CD55 promoter activity was determined by genetic knockdown of PU.1 using small interfering RNAs under specific monocyte activation conditions.

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About the authors

A. N. Uvarova

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Author for correspondence.
Email: uvarowww@gmail.com

Center for Precision Genome Editing and Genetic Technologies for Biomedicine

Russian Federation, Moscow, 119991

E. A. Tkachenko

Engelhardt Institute of Molecular Biology Russian Academy of Sciences; Lomonosov Moscow State University

Email: uvarowww@gmail.com

Faculty of Biology, Lomonosov Moscow State University

Russian Federation, Moscow, 119991; Moscow, 119234

E. M. Stasevich

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: uvarowww@gmail.com

Center for Precision Genome Editing and Genetic Technologies for Biomedicine

Russian Federation, Moscow, 119991

E. A. Bogomolova

Engelhardt Institute of Molecular Biology Russian Academy of Sciences; Moscow Institute of Physics and Technology, Department of Molecular and Biological Physics

Email: uvarowww@gmail.com
Russian Federation, Moscow, 119991; Moscow, 141701

E. A. Zheremyan

Engelhardt Institute of Molecular Biology Russian Academy of Sciences; Lomonosov Moscow State University

Email: uvarowww@gmail.com

Faculty of Biology, Lomonosov Moscow State University

Russian Federation, Moscow, 119991; Moscow, 119234

D. V. Kuprash

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Lomonosov Moscow State University; Moscow Institute of Physics and Technology

Email: uvarowww@gmail.com

Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; Faculty of Biology, Lomonosov Moscow State University; Moscow Institute of Physics and Technology, Department of Molecular and Biological Physics

Russian Federation, Moscow, 119991; Moscow, 119234; Moscow, 141701

K. V. Korneev

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; National Research Center for Hematology

Email: uvarowww@gmail.com

Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Russian Federation, Moscow, 119991; Moscow, 125167

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Supplementary files

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2. Fig. 1. Schematic representation of the location of rs2564978 in the CD55 gene promoter visualized using UCSC Genome Browser (GRCh38/hg38). The CD55 gene promoter region is shown in blue. The red vertical line indicates the location of the rs2564978 single nucleotide polymorphism. Histograms show the locations of histone modifications associated with active regulatory regions of the genome (mono/trimethylation of H3K4, acetylation of H3K27; Roadmap) in CD14+ monocytes. Rectangles mark DNase I hypersensitivity clusters in CD14+ monocytes and transcription factor binding sites (ChIP-seq ENCODE). ChromHMM characterizes chromatin activity in several subsets of CD14+ monocytes (according to Roadmap data): red and orange indicate promoter-like regions, yellow – enhancer-like regions.

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3. Fig. 2. CD55 gene promoter activity is reduced in the presence of the minor rs2564978(T) allele in a macrophage cell model. a – Schematic of the pGL3-basic luciferase reporter construct containing the CD55 gene promoter with alternative rs2564978 alleles. b – Stimulation of U937 monocytes with PMA or PMA+LPS increases the allele-dependent difference in CD55 promoter activity. Expression of the luciferase reporter was normalized to the expression of the internal control luciferase (Renilla). c – Relative expression of CD55 mRNA in unactivated U937 (PBS) and after stimulation with PMA or PMA+LPS. The graphs show the results of three experiments as mean values ​​± SEM. *P < 0.05 – difference between rs2564978(C) and rs2564978(T) variants, ###P < 0.0001 – difference between unstimulated (PBS) and activated cells (unpaired Student’s t-test).

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4. Fig. 3. Genetic knockdown of PU.1 (SPI1) in activated U937 monocytes reduces the activity of the CD55 promoter containing the major rs2564978(C) allele. a – Logo diagram of the PU.1 (SPI1) binding site from the HOCOMOCO v11 database and superimposed CD55 promoter sequences containing different rs2564978 alleles (highlighted in color). P-values ​​of motifs that characterize the predicted binding specificity of PU.1 for alternative alleles are shown above the sequences. b – Relative expression level of SPI1 mRNA in non-activated U937 (PBS), in PMA-stimulated or PMA+LPS-stimulated U937 monocytes. *P < 0.05 – difference between the level of SPI1 mRNA expression in PMA+LPS-stimulated U937 monocytes and in non-activated U937 (unpaired Student’s t-test). c – Relative level of SPI1 mRNA expression in U937 cells upon SPI1 knockdown. *P < 0.05 (unpaired Student’s t-test). d – Relative level of reporter luciferase activity under the CD55 promoter with different rs2564978 variants upon SPI1 knockdown in activated U937 cells. Normalization to the luciferase activity of the internal control. Unmodified cells (control) and cells transfected with non-specific siRNA (siRNA-scr) served as controls. *P < 0.05 – difference between rs2564978(C) and rs2564978(T) variants (unpaired Student’s t-test). #P < 0.05 – difference between rs2564978(C) variant in SPI1 knockdown, control and siRNA-scr. d – Relative level of CD55 mRNA expression in SPI1 knockdown. Mean values ​​± SEM calculated from three experiments are presented.

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5. Fig. 4. Hypothetical scheme of the allele-specific influence of rs2564978 on the development of pathological complications associated with hyperactivation of the complement system (image made using BioRender.com).

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