Abstract 4140468: Tet Methylcytosine Dioxygenase 2 mutation drives a global hypermethylation signature in patients with pulmonary arterial hypertension resulting in a common T cell phenotype.
Bibliographic record
Abstract
Background: Epigenetic changes in gene expression due to DNA methylation regulate pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation or demethylation promote development of pulmonary arterial hypertension (PAH). However, the DNA methylome signature of human PAH and its transcriptomic consequences are unknown. Methods: Reduced Representation Bisulfite Sequencing was used for epigenome-wide mapping of DNA methylation in whole peripheral blood of 10 healthy people and 20 age/sex matched PAH patients from the PAH Biobank. We used whole-exome sequencing to identify two PAH cohorts, one free of mutations of know PAH-associated gene variants, and a second with mutations of TET2 , a newly identified PAH gene that encodes TET2, which mediates DNA demethylation. Results: Patients carrying TET2 mutations had greater DNA CpG methylation compared to mutation-free PAH patients, who themselves had increased methylation compared to controls. Differentially Methylated Regions (DMR) were more common in patients with PAH with TET2 mutations (1,135 DMR) than without mutations (260 DMR). In a public, blood-derived, PAH transcriptomic dataset, we assayed for transcript downregulation of genes that were hypermethylated in our cohort. 161 TET2 DMRs (38 of which were common to PAH without TET2 mutation) corresponded to downregulated transcripts. Functional analysis of the hypermethylated genes in TET2 patients revealed similar conserved functions, related to T cell differentiation and metabolism. Functional comparison of the 38 hypermethylated genes found in both PAH cohorts and the 161 hypermethylated genes unique to TET2 mutation also revealed regulation of T cell pathways. The most hypermethylated and downregulated genes was transcription factor 7 (TCF7), a regulator of T cell differentiation, which would be predicted to promote inflammation. Conclusion: Pan-chromosomal hypermethylation in PAH is greatest in patients with TET2 mutations. Gene hypermethylation may contribute to hallmarks of PAH, including alterations in immune function, T cell differentiation, and metabolism.
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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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".