{"doi":"10.1101/2025.05.06.651484","title":"miRNA-mRNA network analysis identifies PAX5 as a potential regulator of adaptive immune response in COPD","abstract":"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 FEV 1 /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 FEV 1 /FVC) and miRNAs (and mRNAs) in the other group having overall higher expression in controls (increasing FEV 1 /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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557777,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9448,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320640,"name":"Margherita De Marzio","orcid":"0000-0003-1821-208X","position":1,"is_corresponding":false},{"id":267144,"name":"Brian D. Hobbs","orcid":"0000-0001-9564-0745","position":2,"is_corresponding":false},{"id":24971,"name":"Craig P. Hersh","orcid":"0000-0002-1342-4334","position":3,"is_corresponding":false},{"id":1013769,"name":"Min Hyung Ryu","orcid":"0000-0003-3071-7363","position":4,"is_corresponding":false},{"id":226260,"name":"Marieke L. Kuijjer","orcid":"0000-0001-6280-3130","position":5,"is_corresponding":false},{"id":91951,"name":"Michael H. Cho","orcid":null,"position":6,"is_corresponding":false},{"id":267133,"name":"Matthew Moll","orcid":"0000-0002-0683-0975","position":7,"is_corresponding":false},{"id":642258,"name":"Courtney Tern","orcid":"0000-0001-5029-595X","position":8,"is_corresponding":false},{"id":77979,"name":"Peter J. Castaldi","orcid":"0000-0001-9920-4713","position":9,"is_corresponding":false},{"id":36157,"name":"Kimberly Glass","orcid":"0000-0003-4394-5779","position":10,"is_corresponding":false},{"id":242689,"name":"Michele Gentili","orcid":"0000-0003-2282-2227","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40654788","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}