Hypermethylation of the HLA-G promoter is associated with preeclampsia

Tang, Yao; Liu, Haiyan; Li, Han; Peng, Ting; Gu, Weirong; Li, Xiaotian

doi:10.1093/molehr/gav037

Cited by 46 publications

(34 citation statements)

References 35 publications

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“…According to the results of a PCR array analysis of epigenetic modification enzymes, the expression of DNMT1 was altered to the greatest extent in the BPA-induced preeclampsia-like mouse model, whereas the levels of DNMT3a and -3b and TET1, -2, and -3 were not affected. This finding indicates a role for DNMT1-mediated methylation reprogramming, which is manifested in the placentas of women with preeclampsia (37). Using HTR8/ SVneo cells, we confirmed that BPA exposure downregulates WNT signaling by increasing DNA methylation in the promoter region of the WNT2 gene through DNMT1.…”

Section: Discussionsupporting

confidence: 64%

Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation ofWNT2

Tang

Xiong

et al. 2018

FASEB j.

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Preeclampsia leads to adverse outcomes for pregnant women. Bisphenol A (BPA) is an environmental endocrine disruptor and has been shown to be positively associated with increased risk of preeclampsia in human studies. We investigated whether BPA exposure causes preeclampsia‐like features in pregnant mice and the associated underlying mechanisms. Experiments were performed in animal models and cell cultures. In pregnant mice, BPA‐exposed mice exhibited preeclampsia‐like features including hypertension, disruption of the circulation, and the placental angiogenesis biomarkers fms‐related tyrosine kinase 1 and placenta growth factor, and glomerular atrophy; urinary protein was not affected. These preeclampsia‐like features correlated with increased retention of smooth muscle cells and reduced vessel areas at the junctional zone of the placenta. In addition, there were disrupted expression of invasion‐related genes including increased tissue inhibitors of metalloproteinases, decreased metalloproteinases, and Wnt family member WJVT2/β‐catenin, which correlated with increased DNA methylation in its promoter region and upregulation of DNA methyltransferase (Dnmt)l. BPA exposure impeded the interaction between the human cytotrophoblast cell line, HTR‐8/SVneo, and endothelium cells. BPA exposure down‐regulated WNT2 expression, and elevated the DNA methylation of WNT2; these results were consistent with in vivo observations. Inhibition of DNMT in HTR‐8/SVneo cells resulted in reduced DNA methylation and increased expression of WNT2. Taken together, these data demonstrate that BPA exposure alters trophoblast cell invasion and causes abnormal placental vessel remodeling, both of which lead to the development of preeclampsia‐like features in pregnant mice. Our results suggest that this phenomenon involves the epigenetic reprogramming and down‐regulation of WNT2 mediated by DNMT1.—Ye, Y., Tang, Y., Xiong, Y., Feng, L., Li, X. Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation of WNT2. FASEB J. 33,2732–2742 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 64%

Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation ofWNT2

Tang

Xiong

et al. 2018

FASEB j.

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“…The pathophysiological mechanism behind would be a reduced expression of HLA‐G associated with certain HLA‐G gene polymorphisms and haplotypes as described above. Such an aberrant or reduced expression of HLA‐G has also been observed in preeclampsia in many other studies , which in theory would result in disturbances in the immunological fetomaternal crosstalk. The results of the current large and comprehensive study do not indicate that specific basic fetal HLA‐G gene sequence variation with relevance for the HLA‐G protein expression by the trophoblast cells in the placenta explain the low expression of HLA‐G in cases of severe preeclampsia.…”

Section: Discussionsupporting

confidence: 57%

“…One study found that the HLA-G promoter region was significantly more methylated in cases of preeclampsia compared with controls. This was associated with reduced HLA-G expression (63). Another of our own recent studies reported the phenomenon of allelic imbalance in HLA-G 14-bp ins/del heterozygous first trimester trophoblast cells (58).…”

Section: Discussionmentioning

confidence: 84%

Distribution of HLA‐G extended haplotypes and one HLA‐E polymorphism in a large‐scale study of mother–child dyads with and without severe preeclampsia and eclampsia

Nilsson

Djurisic

Andersen

et al. 2016

HLA

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The etiological pathways and pathogenesis of preeclampsia have rendered difficult to disentangle. Accumulating evidence points toward a maladapted maternal immune system, which may involve aberrant placental expression of immunomodulatory human leukocyte antigen (HLA) class Ib molecules during pregnancy. Several studies have shown aberrant or reduced expression of HLA-G in the placenta and in maternal blood in cases of preeclampsia compared with controls. Unlike classical HLA class Ia loci, the nonclassical HLA-G has limited polymorphic variants. Most nucleotide variations are clustered in the 5'-upstream regulatory region (5'URR) and 3'-untranslated regulatory region (3'UTR) of HLA-G and reflect a stringent expressional control. Based on genotyping and full gene sequencing of HLA-G in a large number of cases and controls (n > 900), the present study, which to our knowledge is the largest and most comprehensive performed, investigated the association between the HLA-G 14-bp ins/del (rs66554220) and HLA-E polymorphisms in mother and newborn dyads from pregnancies complicated by severe preeclampsia/eclampsia and from uncomplicated pregnancies. Furthermore, results from extended HLA-G haplotyping in the newborns are presented in order to assess whether a combined contribution of nucleotide variations spanning the 5'URR, coding region, and 3'UTR of HLA-G describes the genetic association with severe preeclampsia more closely. In contrast to earlier findings, the HLA-G 14-bp ins/del polymorphism was not associated with severe preeclampsia. Furthermore, the polymorphism (rs1264457) defining the two nonsynonymous HLA-E alleles, HLA-E*01:01:xx:xx and HLA-E*01:03:xx:xx, were not associated with severe preeclampsia. Finally, no specific HLA-G haplotypes were significantly associated with increased risk of developing severe preeclampsia/eclampsia.

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“…40 Increased DNMT1 and DNMT3B correlate with decreased expression of syncytin-1, GATAD1, and HLA-G in preeclamptic placentas, which are key factors in trophoblast. [41][42][43] These findings stimulate interest in investigating the roles of DNMT1 and DNMT3B in PE in future studies.…”

Section: Discussionmentioning

confidence: 88%

Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia

Jia

Huang

et al. 2017

Hypertension

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Abstract-Preeclampsia is a unique multiple system disorder during human pregnancy, which affects ≈5% to 8% of pregnancies. Its risks and complications have become the major causes of maternal and fetal morbidity and mortality. Although abnormal placentation to which DNA methylation dysregulation is always linked is speculated to be one of the reasons causing preeclampsia, the underlying mechanisms still remain elusive to date. Here we revealed that aberrant DNA methyltransferase 3A (DNMT3A) plays a critical role in preeclampsia. Our results show that the expression and localization of DNMT3A are dysregulated in preeclamptic placenta. Moreover, knockdown of DNMT3A obviously inhibits trophoblast cell migration and invasion. Mechanistically, IGFBP5 (insulin-like growth factor-binding protein 5), known as a suppressor, is upregulated by decreased DNMT3A because of promoter hypomethylation. Importantly, IGFBP5 downregulation can rescue the defects caused by DNMT3A knockdown, thereby, consolidating the significance of IGFBP5 in the downstream of DNMT3A in trophoblast. Furthermore, we detected low promoter methylation and high protein expression of IGFBP5 in the clinical samples of preeclamptic placenta. Collectively, our study suggests that dysregulation of DNMT3A and IGFBP5 is relevant to preeclampsia. Thus, we propose that DNMT3A and IGFBP5 can serve as potential markers and targets for the clinical diagnosis and therapy of preeclampsia.

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Hypermethylation of the HLA-G promoter is associated with preeclampsia

Cited by 46 publications

References 35 publications

Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation ofWNT2

Bisphenol A exposure alters placentation and causes preeclampsia‐like features in pregnant mice involved in reprogramming of DNA methylation ofWNT2

Distribution of HLA‐G extended haplotypes and one HLA‐E polymorphism in a large‐scale study of mother–child dyads with and without severe preeclampsia and eclampsia

Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia

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