Aberrant hydroxymethylation of<i>ANGPTL4</i>is associated with selective intrauterine growth restriction in monochorionic twin pregnancies

Zhang, Yi; Zheng, Dezhong; Fang, Qun; Zhong, Ming

doi:10.1080/15592294.2020.1737355

Cited by 11 publications

(7 citation statements)

References 52 publications

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“…In the analysis of other hypoxia-related factors in twin pregnancies, HIF1α expression was elevated in the placental sector of the smaller fetus in sFGR pregnancies [ 111 , 112 , 113 ], indicating the presence of more severe hypoxia than in an uncomplicated twin pregnancy. The results of aberrant hydroxymethylation of angiopoietin-like 4, a hypoxia-responsive gene regulated by HIF-1α, and increased expression of miR-199a, a master regulator of a hypoxia-triggered pathway targeting HIF-1α in the smaller placental sectors of sFGR, are consistent with the results noted above [ 114 , 115 ]. There is only one report noting evidence that HIF-1α was primarily observed in trophoblastic cells and villus capillary endothelial cells in the donor placenta from TTTS compared with that in the control placenta from non-TTTS twin pregnancies, but the expression of HIF-1α in the recipients tended to be similar to the controls [ 116 ].…”

Section: Hypoxia-related Factorssupporting

confidence: 89%

Molecular Mechanisms Underlying Twin-to-Twin Transfusion Syndrome

Kajiwara

Ozawa

Wada

et al. 2022

Cells

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Twin-to-twin transfusion syndrome is a unique disease and a serious complication occurring in 10–15% of monochorionic multiple pregnancies with various placental complications, including hypoxia, anemia, increased oxidative stress, and ischemia-reperfusion injury. Fetoscopic laser photocoagulation, a minimally invasive surgical procedure, seals the placental vascular anastomoses between twins and dramatically improves the survival rates in twin-to-twin transfusion syndrome. However, fetal demise still occurs, suggesting the presence of causes other than placental vascular anastomoses. Placental insufficiency is considered as the main cause of fetal demise in such cases; however, little is known about its underlying molecular mechanisms. Indeed, the further association of the pathogenic mechanisms involved in twin-to-twin transfusion syndrome placenta with several molecules and pathways, such as vascular endothelial growth factor and the renin–angiotensin system, makes it difficult to understand the underlying pathological conditions. Currently, there are no effective strategies focusing on these mechanisms in clinical practice. Certain types of cell death due to oxidative stress might be occurring in the placenta, and elucidation of the molecular mechanism underlying this cell death can help manage and prevent it. This review reports on the molecular mechanisms underlying the development of twin-to-twin transfusion syndrome for effective management and prevention of fetal demise after fetoscopic laser photocoagulation.

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Section: Hypoxia-related Factorssupporting

confidence: 89%

Molecular Mechanisms Underlying Twin-to-Twin Transfusion Syndrome

Kajiwara

Ozawa

Wada

et al. 2022

Cells

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“…The exact pathogenesis of sIUGR in twin pregnancy remains unknown, though uneven placental sharing and vascular anastomoses appear relevant [4][5][6]. Given that monochorionic twins have identical genetic information, the role of epigenetic factors warrants serious consideration.…”

Section: Discussionmentioning

confidence: 99%

“…Selective intrauterine growth restriction (sIUGR) occurs in approximately 10%-15% of monochorionic twins and frequently causes perinatal morbidity and mortality [1,2]. The mechanisms underlying this disorder remain unclear because monochorionic twins originate from the same zygote and have identical genomes [3,4]. Considering the contribution of unequal placental sharing and vascular anastomoses to inconsistent fetal development [4][5][6], it is reasonable to speculate that the pathogenesis may be associated with the transportation of nutrients like amino acids.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms underlying this disorder remain unclear because monochorionic twins originate from the same zygote and have identical genomes [3,4]. Considering the contribution of unequal placental sharing and vascular anastomoses to inconsistent fetal development [4][5][6], it is reasonable to speculate that the pathogenesis may be associated with the transportation of nutrients like amino acids. The sodium-coupled neutral amino acid transporter 1 (SLC38A1), an important amino acid transporter for energy metabolism and cell physiology, has key roles in neurotransmission, embryonic development, and cancer [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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miR-373-3p Regulates the Proliferative and Migratory Properties of Human HTR8 Cells via SLC38A1 Modulation

et al. 2022

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The genetic pathogenesis of selective intrauterine growth restriction (sIUGR) remains elusive, with evidence suggesting an important role of epigenetic factors such as microRNAs. In this study, we explored the relevance of miR-373-3p to the occurrence of sIUGR. Hypoxia enhanced the levels of miR-373-3p and hypoxia-inducible factor (HIF)-1α, while HIF-1α knockdown not only boosted the migration and proliferation of HTR8 cells but also suppressed the hypoxia-induced upregulation of miR-373-3p and SLC38A1. By contrast, HIF-1α overexpression induced miR-373-3p downregulation and SLC38A1 upregulation, reducing cell growth and migration, which could be reversed by a miR-373-3p inhibitor. Importantly, the miR-373-3p inhibitor and mimic reproduced phenomena similar to those induced by HIF-1α downregulation and overexpression, respectively (including altered SLC38A1 expression, mTOR activation, cell growth, and migration). Mechanistically, the miRNA regulated cell behaviors and related mTOR signaling by targeting SLC38A1 expression through an interaction with the 3 ′ -untranslated region of SLC38A1. The placental tissues of smaller sIUGR fetuses exhibited miR-373-3p and HIF-1α upregulation, SLC38A1 downregulation, and activated mTOR. Overall, miR-373-3p appears to restrict the growth and migration of HTR8 trophoblast cells by targeting SLC38A1, as observed in the placental tissues associated with smaller sIUGR fetuses, and it could have utility in the diagnosis and treatment of this disorder.

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“…The decrease in global DNA hydroxymethylation in selective intrauterine growth restriction (sIUGR) placentas was described in a study of MZ twins [ 48 ]. Similarly, Zhang and colleagues also observed a decrease in global 5hmC levels in the smaller placental share of sIUGR pregnancies [ 49 ]. Additionally, the authors observed lower levels of 5hmC in the promoters of ANGPTL4 and HIF1A genes, which are hypoxia-responsive genes that were downregulated in the smaller placental share of sIUGR [ 49 ].…”

Section: Dna Hydroxymethylation In Intrauterine Growth Restriction (I...mentioning

confidence: 91%

The role of DNA hydroxymethylation and TET enzymes in placental development and pregnancy outcome

et al. 2023

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The placenta is a temporary organ that is essential for supporting mammalian embryo and fetal development. Understanding the molecular mechanisms underlying trophoblast differentiation and placental function may contribute to improving the diagnosis and treatment of obstetric complications. Epigenetics plays a significant role in the regulation of gene expression, particularly at imprinted genes, which are fundamental in the control of placental development. The Ten-Eleven-Translocation enzymes are part of the epigenetic machinery, converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). DNA hydroxymethylation is thought to act as an intermediate in the DNA demethylation mechanism and potentially be a stable and functionally relevant epigenetic mark on its own. The role of DNA hydroxymethylation during differentiation and development of the placenta is not fully understood but increasing knowledge in this field will help to evaluate its potential role in pregnancy complications. This review focuses on DNA hydroxymethylation and its epigenetic regulators in human and mouse placental development and function. Additionally, we address 5hmC in the context of genomic imprinting mechanism and in pregnancy complications, such as intrauterine growth restriction, preeclampsia and pregnancy loss. The cumulative findings show that DNA hydroxymethylation might be important for the control of gene expression in the placenta and suggest a dynamic role in the differentiation of trophoblast cell types during gestation.

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Aberrant hydroxymethylation ofANGPTL4is associated with selective intrauterine growth restriction in monochorionic twin pregnancies

Cited by 11 publications

References 52 publications

Molecular Mechanisms Underlying Twin-to-Twin Transfusion Syndrome

Molecular Mechanisms Underlying Twin-to-Twin Transfusion Syndrome

miR-373-3p Regulates the Proliferative and Migratory Properties of Human HTR8 Cells via SLC38A1 Modulation

The role of DNA hydroxymethylation and TET enzymes in placental development and pregnancy outcome

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