Global DNA methylation in placental tissues from pregnant with preeclampsia: A systematic review and pathway analysis

Cruz, Juliana de Oliveira; Conceição, Izabela Mamede Costa Andrade da; Tosatti, Jéssica Abdo Gonçalves; Gomes, Karina Braga; Luizon, Marcelo R.

doi:10.1016/j.placenta.2020.09.004

Cited by 11 publications

(4 citation statements)

References 80 publications

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“…Our findings of increased circulating TIMP‐3 concentration in pre‐eclampsia are in agreement with previous reports describing hypomethylation of the TIMP3 promoter, 21,22 and increased TIMP3 expression in placental tissue from women with pre‐eclampsia 21 . Our previous systematic review showed that DNA methylation is gene‐specific or specific to genomic regions 24 . Similarly, by means of a sub‐analysis of publicly available data deposited in the Gene Expression Omnibus, we have recently shown that DNA hypomethylation is specific for the promoter region of the TIMP3 gene, leading to increased TIMP3 mRNA levels 20 .…”

Section: Discussionsupporting

confidence: 92%

“…21 Our previous systematic review showed that DNA methylation is gene-specific or specific to genomic regions. 24 Similarly, by means of a sub-analysis of publicly available data deposited in the Gene Expression Omnibus, we have recently shown that DNA hypomethylation is specific for the promoter region of the TIMP3 gene, leading to increased TIMP3 mRNA levels. 20 Moreover, the lack of differences on plasma TIMP-3 levels between early-onset pre-eclampsia and late-onset pre-eclampsia reinforces our earlier results regarding DNA methylation and gene expression showing that TIMP-3 is not able to differentiate between these two pre-eclampsia phenotypes.…”

Section: Discussionmentioning

confidence: 95%

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Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Palei

Cruz

Chaguri

et al. 2022

Intl J Gynecology & Obste

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Objective To assess and compare circulating tissue inhibitor of metalloproteinase 3 (TIMP‐3) concentrations between women with pre‐eclampsia and healthy pregnant women. We also aimed to determine the relationships between circulating TIMP‐3 and matrix metalloproteinase 2 (MMP‐2), MMP‐9, TIMP‐1, and TIMP‐2 concentrations in pre‐eclampsia. Methods A primary case–control study included patients with pre‐eclampsia (n = 219) and gestational hypertension (n = 118), healthy pregnant women (n = 214), and non‐pregnant women (n = 66), and a replication case–control study included patients with pre‐eclampsia (n = 177) and healthy pregnant women (n = 124), all from southeastern Brazil. Plasma TIMP‐3, MMP‐2, MMP‐9, TIMP‐1, and TIMP‐2 concentrations were assessed using commercially available enzyme‐linked immunosorbent assay kits, and the relationships between them were analyzed using Spearman's correlation. Results In our primary study, patients with pre‐eclampsia and gestational hypertension exhibited increased TIMP‐3 concentrations compared with healthy pregnant women (both P < 0.0001) and non‐pregnant women (both P < 0.001). These findings were confirmed in the replication study, showing elevated TIMP‐3 concentrations in women with pre‐eclampsia versus healthy pregnant women (P < 0.001). We found no difference in TIMP‐3 concentrations between early‐onset and late‐onset pre‐eclampsia. Moreover, TIMP‐3 concentrations were significantly correlated with plasma concentrations of TIMP‐1 (r = 0.2333; P = 0.0086) and MMP‐2 (r = 0.2159; P = 0.0156) in pre‐eclampsia. Conclusions Circulating TIMP‐3 concentration is increased in women with pre‐eclampsia compared with healthy pregnant women, and it is positively correlated with plasma MMP‐2 and TIMP‐1 concentrations in pre‐eclampsia.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 95%

Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Palei

Cruz

Chaguri

et al. 2022

Intl J Gynecology & Obste

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“…The reinstatement of repressive epigenetic marks on lineage specification genes during subsequent development is instigated by the priming of maternal and ZGA-active transcription factor (TF) [ 44 – 46 ], the binding of polycomb group protein [ 47 – 49 ], and the de novo DNA methylation of CpG-island promoters [ 50 ]. Recent studies have shown that genomic DNA from PE placentas tend to be hypomethylated compared with that from non-PE placentas [ 51 – 53 ], suggesting the occurrence of defects in DNA methylation during placenta development in PE. However, the precise molecular mechanism underlying the epigenetic and developmental alterations in PE remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Disruption of maternal vascular remodeling by a fetal endoretrovirus-derived gene in preeclampsia

Gong,

He,

Jin

et al. 2024

Genome Biol

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Background Preeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown. Results By analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling. Conclusions Our study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal–fetal interface formation.

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“…Early‐onset preeclampsia, defined as presenting before 34 gestational weeks, is reportedly associated with a higher risk of placental abruptions, stroke, acute respiratory distress, and foetal or perinatal death in comparison to late‐onset preeclampsia 3 . Some have suggested that the underlying causes, risk factors, and immunology of these preeclampsia phenotypes differ 4,5 . Despite interest in understanding and preventing early‐onset preeclampsia, no single definition is used in practice or in research 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Evidence of under‐reporting of early‐onset preeclampsia using register data

Rossides

Wikström

Falasinnu

et al. 2021

Paediatric Perinatal Epid

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Background Early‐onset preeclampsia, traditionally defined as presenting before 34 gestational weeks, is associated with even higher risks of perinatal death, placental abruption, and stroke, than late‐onset preeclampsia. Objective We estimated the degree of misclassification in a high‐risk population of lupus pregnancies and a general population comparator when gestational age at delivery defined preeclampsia phenotype compared to first preeclampsia diagnosis. Methods Patients with lupus and general population comparators from Sweden with ≥1 singleton pregnancy in the Medical Birth Register with a documented ICD code for preeclampsia were included (2002‐2016). We used gestational age at delivery (<34 versus ≥34 weeks) to phenotype preeclampsia early‐ versus late‐onset and then reclassified based on first preeclampsia diagnosis date in the Patient Register. We cross‐tabulated the two definitions and calculated sensitivity using the visit‐based definition as the reference standard for general population and lupus pregnancies, overall and among nulliparous women. Results 331 pregnancies were diagnosed with preeclampsia, of which 322 were in both registers. Of those, 58 were early‐onset based on gestational age at delivery (n = 29 in lupus pregnancies). Overall, 9% of early‐onset preeclampsia in lupus (sensitivity 91%, 95% confidence interval [CI] 75, 98) was misclassified as late‐onset compared to 19% in the general population (sensitivity 81%, 95% CI 64, 92). We noted similar misclassification (4% vs 22%) among nulliparous women. Conclusions In the general population, early‐onset preeclampsia was more likely misclassified as late‐onset than in the high‐risk lupus population. Relying on gestational age at delivery to phenotype preeclampsia, this way underestimates the occurrence of early‐onset preeclampsia. This also suggests that the burden of early‐onset preeclampsia as a public health concern may be under‐reported, although this may be more applicable to milder preeclampsia where expectant management is employed. Research of biological and maternal predictors of early‐onset preeclampsia may be dealing with differentially misclassified outcomes or samples.

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Global DNA methylation in placental tissues from pregnant with preeclampsia: A systematic review and pathway analysis

Cited by 11 publications

References 80 publications

Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Disruption of maternal vascular remodeling by a fetal endoretrovirus-derived gene in preeclampsia

Evidence of under‐reporting of early‐onset preeclampsia using register data

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