miRNA-mRNA network analysis identifies PAX5 as a potential regulator of adaptive immune response in COPD

Abstract Micro-ribonucleic acids (miRNAs) are key post-transcriptional regulators of the immune system and may play a role in Chronic Obstructive Pulmonary Disease (COPD). In this paper, we constructed subject-specific miRNA-mRNA regulatory networks using bulk and deconvoluted whole blood RNA-sequencing, whole blood miRNA-sequencing, and B-cell receptor-sequencing data from up to 570 miRNAs, 11,859 mRNAs, and 3,190 participants in the COPDGene study. Analysis of whole blood networks revealed two subnetworks of miRNA-mRNA interactions significantly (FDR<0.05) associated with changes in FEV1/FVC. We found that miRNAs (and mRNAs) in the network-identified groups had distinct expression patterns, with miRNAs (and mRNAs) in one group having overall higher expression in COPD (decreasing FEV1/FVC) and miRNAs (and mRNAs) in the other group having overall higher expression in controls (increasing FEV1/FVC). In addition, miRNAs (and mRNAs) within the same group were positively correlated, while those in different groups were negatively correlated, indicating distinct functional roles for these miRNAs (and mRNAs) as a function of increased COPD severity. Network analysis also identified PAX5, a transcription factor master regulator of B-cell development, as the main mRNA network hub. Using ChIP-seq data in lymphoblastoid cells, we identified a PAX5 binding site overlapping with a COPD genome-wide association signal in the promoter region of ADAM19. We also found a loss of co-expression between PAX5 and ADAM19 in COPD subjects. Furthermore, in B-cell deconvoluted data, PAX5 was differentially co-expressed with genes associated with B-cell activation and differentiation, revealing a possible mechanism for the regulation of the immune response in COPD. Finally, in B-cell receptor sequencing data, PAX5 and the identified mRNA subnetworks were negatively associated (FDR<0.05) with immunoglobulin class switching, and positively associated with IgM and IgD counts. In conclusion, PAX5 is a known regulator of B-cell identity. B cells are recognized as key players in chronic inflammation and immune dysregulation in COPD. Our work suggests that PAX5 plays a mediating role both in ADAM19 regulation and in miRNA regulation of early B cells in COPD. Competing Interest Statement BDH previously received grant support from Bayer, unrelated to this work. CPH has also received funding from the Alpha-1 Foundation and Bayer, unrelated to this work. MHC has received grant support from Bayer and consulting fees from Apogee Therapeutics and Bristol Myers Squibb, unrelated to the current work. PJC has received grant funding from Sanofi and Bayer and consulting fees from Genentech and Verona Pharma, unrelated to this work.