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. 2020 Nov 13;3(1):678.
doi: 10.1038/s42003-020-01411-4.

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma

Britney A Helling  1 , Débora R Sobreira  2 , Grace T Hansen  2 , Noboru J Sakabe  2 , Kaixuan Luo  2 , Christine Billstrand  2 , Bharathi Laxman  3 , Raluca I Nicolae  2 , Dan L Nicolae  4 , Yury A Bochkov  5 , James E Gern  5 , Marcelo A Nobrega  2 , Steven R White  3 , Carole Ober  2
Affiliations

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma

Britney A Helling et al. Commun Biol. .

Abstract

There is a life-long relationship between rhinovirus (RV) infection and the development and clinical manifestations of asthma. In this study we demonstrate that cultured primary bronchial epithelial cells from adults with asthma (n = 9) show different transcriptional and chromatin responses to RV infection compared to those without asthma (n = 9). Both the number and magnitude of transcriptional and chromatin responses to RV were muted in cells from asthma cases compared to controls. Pathway analysis of the transcriptionally responsive genes revealed enrichments of apoptotic pathways in controls but inflammatory pathways in asthma cases. Using promoter capture Hi-C we tethered regions of RV-responsive chromatin to RV-responsive genes and showed enrichment of these regions and genes at asthma GWAS loci. Taken together, our studies indicate a delayed or prolonged inflammatory state in cells from asthma cases and highlight genes that may contribute to genetic risk for asthma.

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Conflict of interest statement

J.E.G. reports consulting fees from Regeneron, consulting fees and stock options from Meissa Vaccines Inc and consulting fees from MedImmune/AstraZeneca outside the submitted work. In addition, J.E.G. has two patents on methods for propagating rhinovirus-C species viruses. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Different transcriptional responses to RV in asthma cases and controls.
Volcano plots showing the log-fold transcriptional changes to RV (x-axis) in controls (A) and cases (B) at FDR < 0.05 (dashed horizontal line). C The log fold change in the 1929 genes that are differentially expressed in both cases (x-axis) and controls (y-axis). Gray points indicate genes with greater log fold change in controls; burgundy points indicate genes with greater log fold change in cases. Arrows point to black dots representing the thirteen genes with opposite direction of effect in cases and controls.
Fig. 2
Fig. 2. Pathway and gene-ontology network enrichments for RV-responsive genes in cases and controls.
RV-responsive pathways in controls (A) and cases (B). GO identified biological processes enriched in controls (C) or cases (D). Twenty-eight additional terms were enriched in both cases and controls (see Supplementary Data 3). Bonferroni adjusted p values shown.
Fig. 3
Fig. 3. Chromatin accessibility response to RV.
RV infection results in 2458 differentially accessible chromatin regions in controls (five nonsignificant values were outside the range of the x-axis and are not shown) (A) and 238 in asthma cases (10 nonsignificant values were outside the range of the x-axis and are not shown) (B); (FDR < 0.05). C Fold changes for the 58 regions of RV-responsive chromatin accessibility. Gray dots represent greater change in chromatin accessibility in controls and burgundy dots represent greater change in cases.
Fig. 4
Fig. 4. HOMER motif analysis shows enrichments of TFBS in areas of RV-responsive open chromatin.
A RV-responsive areas of open chromatin have been separated by those with increased accessibility and decreased accessibility in the RV-treated sample in the first column of the table. The number of enriched TFBS and the corresponding number of unique TF identified by HOMER (in parentheses) are shown in the second column of the table. The last column indicates the number (percent in parentheses) of unique transcription factors identified by HOMER that are also RV-responsive. B The five most enriched TFBS are shown for areas with increased accessibility in RV-treated samples from controls. The black bars indicate the % of regions containing the motif among all ATAC-seq peaks and the grey bar indicates the % of regions containing the motif in the RV-responsive areas of open chromatin. Panels C and D show the five most enriched TFBS for the areas with decreased accessibility in controls and increased accessibility in cases, respectively. *HOMER identified TFBS that correspond to transcription factors that also have RV-responsive gene expression.
Fig. 5
Fig. 5. RV-responsive areas of open chromatin correlated with gene expression at pcHi-C predicted target genes.
A The numbers of RV-responsive genes, chromatin regions, or pcHi-C target genes of RV-responsive chromatin regions in controls (gray) and cases (burgundy) and both (white) are shown in the first three columns. The last column shows the number the pcHi-C predicted genes where the chromatin accessible and gene expression were correlated (Spearman’s correlation, FDR adj. p < 0.05). B The promoter of PLAUR loops to an area of open chromatin at chr19:43967179–43968550. Chromatin accessibility for each condition is shown in the top panel, gene expression in the second panel and the bottom panel indicates pcHi-C looping from the PLAUR promoter. The pink box indicates the PLAUR promoter, the blue box indicates the RV-responsive area of open chromatin. C Correlation between expression of PLAUR and chromatin accessibility at chr19:43967179–43968550. D, E are gene-chromatin pairs where the gene is RV-responsive in both cases and controls while the chromatin is only RV-responsive in the controls.
Fig. 6
Fig. 6. A total of 141 RV-responsive genes in cases or controls overlap with previously defined asthma-GWAS loci.
Thirty-nine of these genes interact with at least one other of the 141 genes, forming four networks annotated by iPathwayGuide. The genes are color coded to show genes within shared loci; gray genes are all within the HLA region on 6p21.32, purple are within 17q12, green are within 1q21.3, pink are within 12q13.2, yellow is within 7p15.3, orange is within 10p14, yellow–green is within 18q21.33, blue are within 5q31.1, and teal is within 13q32.3. The shape of the gene indicates differential expression between cases and controls (FDR < 0.05); shape 1 indicates no change in expression between cases and controls, shape 2 indicates increased expression in cases compared to controls, and shape 3 indicates decreased expression in cases compared to controls.
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