miRNA-mRNA Network Analysis Identifies PAX5 as a Potential Regulator of Adaptive Immune Response in COPD
Bibliographic record
Abstract
Abstract RationaleIn Chronic Obstructive Pulmonary Disease (COPD), environmental insults trigger both chronic and acute inflammatory responses. Recent research highlights micro-ribonucleic acids (miRNAs) as crucial post-transcriptional regulators of the immune system. MethodsWe employed two algorithms developed in our lab, PUMA and LIONESS, to infer subject-specific miRNA-mRNA regulatory networks using whole blood RNA-seq data from 3,190 participants in the COPDGene study. We applied linear modeling to identify miRNA-mRNA edges significantly (FDR<0.05) associated with FEV1/FVC[asterisk] and performed enrichment analysis to determine the functions associated with target mRNAs. We analyzed the expression patterns of the regulating miRNAs (570 miRNAs) using miRNA-seq expression data collected in 332 of the analyzed COPDGene subjects and 570 miRNAs. Lastly we leverage B-cell receptor-seq data collected on 137 subjects present in our cohort, to find significant associations (FDR<0.05) between PAX5 and B-cell functions. Results Our analysis uncovered a subnetwork of miRNA – mRNA interactions (n=2,873) between 131 miRNAs and 217 mRNAs, significantly associated (FDR < 0.05) with changes in FEV1/FVC. Network analysis identified two modules whose members exhibited negative co-expression in whole blood, indicating a potential switching mechanism correlated with COPD severity. PAX5, a transcription factor essential for the maturation of pre-B and pro-B cells, was downregulated with increasing COPD severity and was found to be a key mRNA hub of the regulatory network. Additional analysis of B-cell receptor sequencing data revealed that PAX5 was significantly associated (FDR < 0.05) with V(D)J recombination, class switch recombination, and IgM and IgD expression, indicating miRNA dysregulation during early B-cell activation in COPD. PAX5 also showed differential co-expression with genes linked to B-cell activation and differentiation.Finally, using publicly available ChIP-seq data for lymphoblastoid cells, we identified a direct overlap between a PAX5 binding site and a COPD-associated GWAS SNP in the promoter region of ADAM19. We also found a loss of co-expression between PAX5 and ADAM19 in COPD patients, suggesting a novel regulatory mechanism influencing immune responses in COPD. ConclusionsIn conclusion, PAX5 is a known regulator of B-cell identity and B cells are recognized as key players in chronic inflammation and immune dysregulation in COPD. Our work bridges this connection by hypothesizing that PAX5 may play a mediating role in miRNA regulation for B cells in COPD. [asterisk]FEV1: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".