S156 IPF associated DNA methylation and gene expression changes in lung fibroblasts: airway and parenchymal distinction and XY chromosome profiling
Bibliographic record
Abstract
Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease, that is predominant in men and has been associated with cell specific alterations to DNAm. Fibroblasts isolated from airways (AF) and parenchyma (PF) are phenotypically different. While most DNAm studies discard XY chromosome data during preprocessing, due to difference in profile compared to autosomal chromosomes, we developed a pipeline to interrogate XY DNAm. Here we investigated differential IPF associated gene expression (GE) and DNAm in AF and PF, including the XY chromosomes. Methods DNA and RNA were isolated from AF (8 non-IPF, 8 IPF) and PF (14 non-IPF, 8 IPF) at passage 4 (AllPrep DNA/RNA Mini Kit (Qiagen)). DNA was bisulphite-converted and DNAm profiled using the Illumina HumanMethylation EPIC BeadChip array. RNA was profiled by Affymetrix Human Gene 2.1 ST Array. IPF associations irrespective of fibroblast type (~Disease+CellType+Gender+Age) and specific to fibroblast type (~Disease*CellType+Gender+Age) were identified by linear modelling of autosomal and male X and male Y chromosomes separately (Benjamini-Hochberg, p<0.05). Expression quantitative trait methylation (eQTM) was used to investigate the association between differential GE and DNAm. Results On autosomal chromosomes, 12,287 probes and 166,329 methylation sites (CpGs) were differentially expressed and methylated in IPF fibroblasts compared to non-IPF fibroblasts, regardless of subtype (AF/PF). 92.87% of differentially expressed probes correlated with a methylation change in at least one CpG site (10,209,277 individual CpG-gene pairs). 249 probes and 20,522 CpGs were differentially associated with IPF in AF versus PF. 93.98% of cell specific IPF associated gene expression probes correlated with a methylation change (846,718 CpG-gene pairs). On the male X chromosome 4159 of 16,217 CpGs and 212 of 1542 probes showed differential methylation and expression in IPF versus non-IPF fibroblasts. On the male Y chromosome, 13 CpGs and 39 probes were differentially methylated and expressed. Fibroblast sub-type had minimal impact on differential expression and methylation on XY chromosomes. Conclusion DNAm is potentially an important cell-specific mechanism underlying differential GE in IPF, including changes on the XY chromosomes. Future work will further define XY chromosome DNAm and GE associations, and functionally characterise the role of DNAm in IPF GE in vitro.
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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) | 0.016 | 0.003 |
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".