Tet Methylcytosine Dioxygenase 2 (<scp><i>TET2</i></scp>) Mutation Drives a Global Hypermethylation Signature in Patients With Pulmonary Arterial Hypertension (<scp>PAH</scp>): Correlation With Altered Gene Expression Relevant to a Common T Cell Phenotype
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Bibliographic record
Abstract
Epigenetic changes in gene expression due to DNA methylation regulate pulmonary vascular structure and function. Genetic or acquired alterations in DNA methylation/demethylation can promote the development of pulmonary arterial hypertension (PAH). Here, we performed epigenome-wide mapping of DNA methylation in whole blood from 10 healthy people and 19 age/sex-matched PAH patients from the PAH Biobank. Exome sequencing confirmed the absence of known mutations in PAH-associated gene variants identifying subjects with or without mutations of TET2, a putative PAH gene encoding the demethylating enzyme, TET2. DNA of patients with PAH and no TET2 mutation was hypermethylated compared to healthy controls. Patients with PAH and a TET2 mutation had greater DNA CpG methylation than mutation-free PAH patients. Unique Differentially Methylated Regions (DMR) were more common in patients with PAH with TET2 mutations (1164) than in PAH without mutations (262). We correlated methylome findings with a public PAH transcriptomic RNA dataset, prioritizing targets that are both hypermethylated in our cohort and downregulated at the RNA level. Relative to controls, functional analysis reveals enriched functions related to T cell differentiation in PAH patients with a TET2 mutation. We identified genes with downregulated expression that were hypermethylated in PAH patients (with or without a TET2 mutation). In both cases, a conserved T cell phenotype emerged. Pan-chromosomal hypermethylation in PAH is greatest in patients with TET2 mutations. Observed hypermethylation of genes involved in the pathogenesis of PAH, such as EIF2AK4, and transcription factors that regulate T cell development, such as TCF7, merit further study and may contribute to the inflammation in PAH.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it