ArticleProceedings of the National Academy of Sciences of the United States of America2016
HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers, 1 of them a synthesis that pooled it.
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Who cites it
83 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- Knowledge-Driven Mechanistic Enrichment of the Preeclampsia Ignorome.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2023Pooled it
- Understanding physiological adaptations of pregnancy to the chronic hypoxia of high altitude to inform obstetrical and neonatal care.Physiological reviews · 2026Review
- PPARG directs trophoblast cell fate and establishment of the uterine-placental interface.EMBO reports · 2026Article
- UBE2M deficiency in alveolar macrophages promotes emphysema through HIF-2α/MMP12 axis.Chinese medical journal pulmonary and critical care medicine · 2026Article
- Fundamental and unique roles of PLAC1 in the regulation of rat and human trophoblast cell development.Development (Cambridge, England) · 2026Article
- Conserved gene expression patterns in the placenta underlie pregnancy complications associated with hypoxia in mice and humans.Cellular and molecular life sciences : CMLS · 2026Article
- Histone post-translational modifications in diabetic foot ulcer healing: linking immune dysregulation to tissue repair.Frontiers in immunology · 2026Review
- Trophoblast adaptation to hypoxia: balance and dysfunction.Cell communication and signaling : CCS · 2025Review
- Maternal Diet-Induced Excess Adiposity in Mice Disrupts Mid-Gestation Decidual Immune and Vascular Homeostasis Without Impairing Spiral Artery Remodeling.Acta physiologica (Oxford, England) · 2025Article
- PPARG directs trophoblast cell fate and establishment of the uterine-placental interface.bioRxiv : the preprint server for biology · 2025Article
- A Feedback Loop Between Fatty Acid Metabolism and Epigenetics in Clear Cell Renal Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Super-Enhancers in Placental Development and Diseases.Journal of developmental biology · 2025Review
- Extracellular Vesicles Alter Trophoblast Function in Pregnancies Complicated by COVID-19.Journal of extracellular vesicles · 2025Article
- In vitro differentiation of macaque extravillous trophoblasts in a low oxygen environment.Placenta · 2025Article
- Roles and mechanisms of histone methylation in vascular aging and related diseases.Clinical epigenetics · 2025Review
- Identification of metabolism-related subtypes and feature genes of pre-eclampsia.Scientific reports · 2025Article
- C3AR1 as a target for preeclampsia: from bioinformatics and network pharmacology to experimental validation.BMC pregnancy and childbirth · 2025Article
- Article
- A comprehensive review of the roles of T-cell immunity in preeclampsia.Frontiers in immunology · 2025Review
- Exploring transcriptomic mechanisms underlying pulmonary adaptation to diverse environments in Indian rams.Molecular biology reports · 2024Article
23 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
The hemochorial placenta develops from the coordinated multilineage differentiation of trophoblast stem (TS) cells. An invasive trophoblast cell lineage remodels uterine spiral arteries, facilitating nutrient flow, failure of which is associated with pathological conditions such as preeclampsia, intrauterine growth restriction, and preterm birth. Hypoxia plays an instructive role in influencing trophoblast cell differentiation and regulating placental organization. Key downstream hypoxia-activated events were delineated using rat TS cells and tested in vivo, using trophoblast-specific lentiviral gene delivery and genome editing. DNA microarray analyses performed on rat TS cells exposed to ambient or low oxygen and pregnant rats exposed to ambient or hypoxic conditions showed up-regulation of genes characteristic of an invasive/vascular remodeling/inflammatory phenotype. Among the shared up-regulated genes was matrix metallopeptidase 12 (MMP12). To explore the functional importance of MMP12 in trophoblast cell-directed spiral artery remodeling, we generated an Mmp12 mutant rat model using transcription activator-like nucleases-mediated genome editing. Homozygous mutant placentation sites showed decreased hypoxia-dependent endovascular trophoblast invasion and impaired trophoblast-directed spiral artery remodeling. A link was established between hypoxia/HIF and MMP12; however, evidence did not support Mmp12 as a direct target of HIF action. Lysine demethylase 3A (KDM3A) was identified as mediator of hypoxia/HIF regulation of Mmp12 Knockdown of KDM3A in rat TS cells inhibited the expression of a subset of the hypoxia-hypoxia inducible factor (HIF)-dependent transcripts, including Mmp12, altered H3K9 methylation status, and decreased hypoxia-induced trophoblast cell invasion in vitro and in vivo. The hypoxia-HIF-KDM3A-MMP12 regulatory circuit is conserved and facilitates placental adaptations to environmental challenges.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.