JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration

Alahari, Sruthi; Farrell, Abby; Ermini, Leonardo; Park, Chanho; Sallais, Julien; Roberts, Sarah; Gillmore, Taylor; Litvack, Michael; Post, Martin; Caniggia, Isabella

doi:10.3389/fcell.2021.652607

Cited by 8 publications

(14 citation statements)

References 70 publications

(104 reference statements)

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“…Hypoxia is a potent regulator of extracellular matrix-associated proteins, including FN ( 40 , 41 ). Hence, we investigated whether hypoxia, a characteristic of PE placentae ( 27 , 42 ), contributed to the striking changes in sEV FN in PE. WB for FN in sEVs isolated from conditioned media from JEG3 cells maintained in hypoxia (3% O 2 ) revealed that low oxygen exposure significantly stimulated FN release via sEVs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Considering our recent observation that the oxygen- and iron-dependent lysyl hydroxylase JMJD6 is a negative regulator of FN ( 27 ), we examined whether altered JMJD6 expression and function may also impinge on sEV FN in PE. Following siRNA knockdown of JMJD6 in JEG3 cells, attenuation of JMJD6 levels was corroborated by WB for JMJD6 (Supplementary Figure 4B ( 28 )), while NTA ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Because sEV cargo reflects the tissue of origin, we used placental sEVs isolated from maternal sera of normal and pathological (E-PE, L-PE, and gestational hypertension [GH]) pregnancies throughout gestation as readouts of placental FN homeostasis and examined their potential to serve as a putative biomarker for PE. We recently reported that the oxygen sensor Jumonji C domain containing protein 6 (JMJD6) controls FN processing and turnover in the placenta in an iron-dependent manner ( 27 ). Hence, we further investigated whether JMJD6 regulation of FN by oxygen and iron contributes to altered FN cargo in placental sEVs in preeclampsia.…”

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confidence: 99%

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Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia

et al. 2023

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Preeclampsia (PE) is a major obstetric complication that is challenging to predict. Currently, there are limited tools to assess placental health/function in crucial gestational periods for diagnosis and early prediction. The glycoprotein fibronectin (FN) is augmented in PE placentae, and associated with reduced activity of JMJD6, an oxygen sensor that regulates placental FN processing. Evidence implicates placenta-derived small extracellular vesicles (sEVs) in the pathogenesis of pregnancy-associated disorders. Herein, we examined the utility of FN and JMJD6 in placental sEVs as putative markers for early- and late-onset preeclampsia (E-PE and L-PE). Maternal plasma was obtained from venous blood collected longitudinally during pregnancy (10-14, 16-22, 26-32 weeks of gestation and at delivery) in normotensive term control, pre-term control, L-PE, E-PE and gestational hypertensive individuals. Placenta-derived sEVs were isolated and their FN and JMJD6 content and JMJD6 activity were measured. In women that went on to develop preeclampsia, FN content of circulating placental sEVs was significantly elevated as early as 10-14 weeks of gestation and remained augmented until the time of delivery. This was accompanied by a depletion in JMJD6 content. Multivariate receiver operating characteristic analysis revealed high predictive power for FN and JMJD6 as early markers of E-PE and L-PE. In vitro, hypoxia or JMJD6 loss promoted FN accumulation in sEVs that was reverted upon restoring cellular iron balance with the natural compound, Hinokitiol. Elevated FN, along with diminished JMJD6 in circulating placental sEVs serves as an early molecular signature for the detection of different hypertensive disorders of pregnancy and their severity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia

et al. 2023

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“…Demethylation is an important core epigenetic change that is involved in the regulation of transcription, chromatin structure, epigenetic and genomic integrity by specifically identifying chromatin active regions (21)(22)(23). A large number of studies have shown that JMJD6 is a key regulatory molecule in histone modification (such as diffusion of ubiquitination), transcriptional elongation and RNA splicing (14,24) and that it is required for angiogenesis, cell differentiation and proliferation (25,26). Based on the study of Hu et al, the proliferation of NIH3T3 fibroblast cells with JMJD6 knockdown was markedly reduced (27).…”

Section: Structure and Biological Function Of Jmjd6mentioning

confidence: 99%

Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response

Wang

Yang

Li³

et al. 2022

Front. Immunol.

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JMJD6 is a member of the Jumonji (JMJC) domain family of histone demethylases that contributes to catalyzing the demethylation of H3R2me2 and/or H4R3me2 and regulating the expression of specific genes. JMJD6-mediated demethylation modifications are involved in the regulation of transcription, chromatin structure, epigenetics, and genome integrity. The abnormal expression of JMJD6 is associated with the occurrence and development of a variety of tumors, including breast carcinoma, lung carcinoma, colon carcinoma, glioma, prostate carcinoma, melanoma, liver carcinoma, etc. Besides, JMJD6 regulates the innate immune response and affects many biological functions, as well as may play key roles in the regulation of immune response in tumors. Given the importance of epigenetic function in tumors, targeting JMJD6 gene by modulating the role of immune components in tumorigenesis and its development will contribute to the development of a promising strategy for cancer therapy. In this article, we introduce the structure and biological activities of JMJD6, followed by summarizing its roles in tumorigenesis and tumor development. Importantly, we highlight the potential functions of JMJD6 in the regulation of tumor immune response, as well as the development of JMJD6 targeted small-molecule inhibitors for cancer therapy.

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“…The ability of Hinokitiol to rescue fibronectin assembly and JMJD6 function reveals the possible direction of preeclamptic treatment (Ref. 83).…”

Section: Jmjd6's Role In Preeclampsiamentioning

confidence: 99%

Regulatory role of JMJD6 in placental development

Shen

Geyter

Zhang

et al. 2022

Expert Rev. Mol. Med.

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Correct placental development and function are critical to both the mother's and the foetus' health during pregnancy. Placental function depends on the correct development of the vascular network, which requires proper angiogenesis. Impaired angiogenesis in the placenta can induce foetal growth restriction, preeclampsia, and even foetal death. Placental angiogenesis is finely controlled by ubiquitous and pregnancy-specific angiogenic factors. Jumonji domain-containing protein 6 (JMJD6) is a Fe (II)-and 2-oxoglutarate (2OG)-dependent oxygenase that catalyses arginine demethylation and lysine hydroxylation of histone and non-histone peptides. JMJD6 has been implicated in embryonic development, cellular proliferation and migration, self-tolerance induction in the thymus, and adipocyte differentiation. In this review we present JMJD6's structure and activity, as well as its role in angiogenesis, oxygen sensing, and adverse pregnancy outcomes related to placental development. Understanding the interaction between JMJD6 and other placental factors may identify potential therapeutic targets for correcting abnormal placental angiogenesis and function.

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JMJD6 Dysfunction Due to Iron Deficiency in Preeclampsia Disrupts Fibronectin Homeostasis Resulting in Diminished Trophoblast Migration

Cited by 8 publications

References 70 publications

Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia

Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia

Role of the Epigenetic Modifier JMJD6 in Tumor Development and Regulation of Immune Response

Regulatory role of JMJD6 in placental development

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