The Dynamic Role of Jumonji C Domain Containing Protein 6 in Placental Development and Disease
Bibliographic record
Abstract
Perturbations in oxygen sensing are a defining feature of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Preeclamptic placentae have markedly elevated levels of Hypoxia Inducible Factor 1Îą (HIF1A), a master regulator of oxygen homeostasis. Mounting evidence implicates a family of Fe2+ and oxygen-dependent Jumonji C domain containing enzymes (JMJDs) as mediators of the epigenetic code and hypoxic gene expression. While several JMJDs are induced in hypoxia, their role in pregnancy remains unclear. The goal of this study was to characterize JMJD6 function in the placenta in physiological and pathological conditions, and unravel its regulatory relationship with von Hippel Lindau tumour suppressor (VHL), a key executor of the cellular hypoxic response. JMJD6 expression inversely correlated with changes in oxygen tension during placental development, while JMJD6 protein and mRNA were significantly elevated in low oxygen and in early-onset preeclamptic (E-PE) placentae. In vitro demethylation assays revealed that optimal JMJD6-dependent demethylation of its histone targets, H3R2me2s and H4R3me2s, occurred in normoxia, and this was impaired in E-PE placentae due to a hypoxia-iron imbalance. In cytotrophoblast cells, JMJD6 is a positive regulator of VHL gene expression in normoxia. Accordingly, JMJD6 histone targets in E-PE placentae showed marked reductions in their association with VHL promoter regions. Independent of VHL gene regulation, JMJD6 also controlled VHL protein stability through lysyl hydroxylation and promoting its SUMO1-dependent SUMOylation. Importantly, the Jumonji C catalytic domain was found to be indispensable in executing both functions of JMJD6. In summary, these data signify a novel function for JMJD6 as an oxygen sensor in the human placenta, exerting a dual role in regulating VHL gene and protein. Uncovering epigenetic oxygen sensing mechanisms controlling HIF1A is crucial for defining the unique molecular signature of preeclampsia, which may ultimately translate to molecular-based diagnosis and therapy.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| 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) | 0.001 | 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".