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

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 . 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 ) and miRNAs (and mRNAs) in the other group having overall higher expression in controls (increasing ). 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 , 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 . We also found a loss of co-expression between and in COPD subjects. Furthermore, in B-cell deconvoluted data, 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, 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, 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 plays a mediating role both in regulation and in miRNA regulation of early B cells in COPD.