Altered imprinting, promoter usage, and expression of insulin-like growth factor-II gene in gestational trophoblastic diseases

Kim, Sung J.o; Park, Sang Eun; Lee, Chan; Lee, Sun Young; Kim, I.n H.o; An, Hee Jung; Oh, Yu‐Kyoung

doi:10.1016/s0090-8258(02)00143-9

Cited by 19 publications

(14 citation statements)

References 21 publications

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“…LOI of H19 was observed only in preeclamptic placentas and was correlated with the severity of the disease (23). Similarly, relaxation of the IGF2 imprinting was demonstrated in tissues with gestational trophoblastic disease unlike the normal placentas (24). Since LOI was also established in the affected placentas in our study, we hypothesize that relaxed IGF2 imprinting might correlate with placental dysfunction which represents a component of the original pathogenetic process of FGR.…”

Section: Discussionsupporting

confidence: 66%

“…Whether the observed IGF2 downregulation is a causative factor of FGR or merely a consequence of placental dysfunction remains unexplained. An abnormal biallelic placental expression of imprinted genes has been reported in cases of abnormal placentation such as preeclampsia and gestational trophoblastic disease (23,24). We hypothesize that in FGR cases the placenta responds to chronic hypoperfusion by activating a program of gene expression via genomic imprinting.…”

Section: Discussionmentioning

confidence: 86%

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Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction

Koukoura

Sifakis²,

Soufla³

et al. 2011

Int J Mol Med

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Abstract. The objective of this study was to investigate the hypothesis that the altered epigenetic mechanisms that regulate IGF2 imprinting in placentas from fetal growth restricted (FGR) pregnancies affect IGF2 expression leading to impaired fetal growth. We investigated gene transcription, genotyping and the methylation patterns of IGF2 from 31 and 17 placentas from FGR-complicated and normal pregnancies, respectively. A statistically significant decrease in IGF2 mRNA levels was observed in the placentas from the FGR pregnancies. Loss of imprinting (LOI) was only detected in the abnormal placentas. The evaluation of the percentage of the methylated reference (PMR) of two different potentially differentially methylated regions (DMR) demonstrated significant PMR values in both sites for the normal and FGR pregnancies with no significant differences. Our results suggest the involvement of the IGF2 imprinted gene in placental function and fetal growth and the possible association of epigenetic alterations with the pathophysiology of fetal growth restriction. IntroductionIt is well known that fetal growth restriction (FGR) is not a single disorder, but instead has various causes (1). Placental dysfunction ranks high among the most common causes of FGR. Although numerous placental histopathological changes have been described, little is known about the precise etiology and the contribution of placental genes in this disorder (2,3).Imprinted genes are known to be involved in regulating placental growth and function and are therefore considered to be suitable candidates for a role in FGR development (4,5). Genomic imprinting is the preferential silencing of one copy of an autosomal gene while the other copy is expressed (6). This parent-of-origin-specific expression is regulated by epigenetic modifications, such as DNA methylation. Imprinted genes that are paternally expressed (maternally imprinted) promote growth of the fetus, while maternally expressed (paternally imprinted) genes act as growth suppressors to ensure the appropriate allocation of limited maternal resources to each offspring (7). Insulin-like growth factor 2 (IGF2) and H19 represent two oppositely expressed genes located adjacent to each other at 11p15.5 that share the same transcription regulatory epigenetic mechanisms (8). IGF2 is highly expressed in mouse and human placenta and affects both the functional capacity of the placenta to transfer nutrients to the fetus and placental size (9,10). It is expressed in most tissues only from the paternal allele, with the maternal allele being transcriptionally silent.Imprinting occurs primarily by allelic-specific methylation of cytosines in areas of DNA that are rich in CpG dinucleotides (11). In most human tissues the imprinting of IGF2 depends on a differentially methylated region (DMR) which is located upstream of H19 promoters (12). This region functions as a methylation-sensitive insulator that binds to a CCCTC factor (CTCF) on the unmethylated maternal allele preventing the interaction of IGF2 with t...

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 86%

Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction

Koukoura

Sifakis²,

Soufla³

et al. 2011

Int J Mol Med

View full text Add to dashboard Cite

show abstract

“…Some studies reported that imprinted gene defects lead to early embryonic and fetal death, prolonged labor, and development of embryonic tumors (17,30).…”

Section: Discussionmentioning

confidence: 99%

Assisted reproductive technologies do not increase risk of abnormal methylation of PEG1/MEST in human early pregnancy loss

Zheng

Shi

et al. 2011

Fertility and Sterility

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“…Complete hydatidiform moles (CHM) showed high-level expression of H19 from the paternal allele, while choriocarcinomas developing from CHMs had reduced numbers of H19 -positive cells [23]. H19 downregulation was also observed in gestational trophoblastic tumors [24]. These observations appear to support the notion that H19 functions as a tumor suppressor in trophoblast tissue.…”

Section: Introductionmentioning

confidence: 88%

Lentivirus-mediated RNA interference targeting the H19 gene inhibits cell proliferation and apoptosis in human choriocarcinoma cell line JAR

Chang

et al. 2013

BMC Cell Biol

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BackgroundH19 is a paternally imprinted gene that has been shown to be highly expressed in the trophoblast tissue. Results from previous studies have initiated a debate as to whether noncoding RNA H19 acts as a tumor suppressor or as a tumor promotor in trophoblast tissue. In the present study, we developed lentiviral vectors expressing H19-specific small interfering RNA (siRNA) to specifically block the expression of H19 in the human choriocarcinoma cell line JAR. Using this approach, we investigated the impact of the H19 gene on the proliferation, invasion and apoptosis of JAR cells. Moreover, we examined the effect of H19 knockdown on the expression of insulin-like growth factor 2 (IGF2), hairy and enhancer of split homologue-1 (HES-1) and dual-specific phosphatase 5 (DUSP5) genes.ResultsH19 knockdown inhibited apoptosis and proliferation of JAR cells, but had no significant impact on cell invasion. In addition, H19 knockdown resulted in significant upregulation of HES-1 and DUSP5 expression, but not IGF2 expression in JAR cells.ConclusionsThe finding that H19 downregulation could simultaneously inhibit proliferation and apoptosis of JAR cells highlights a putative dual function for H19 in choriocarcinoma and may explain the debate on whether H19 acts as a tumor suppressor or a tumor promotor in trophoblast tissue. Furthermore, upregulation of HES-1 and DUSP5 may mediate H19 downregulation-induced suppression of proliferation and apoptosis of JAR cells.

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Altered imprinting, promoter usage, and expression of insulin-like growth factor-II gene in gestational trophoblastic diseases

Cited by 19 publications

References 21 publications

Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction

Loss of imprinting and aberrant methylation of IGF2 in placentas from pregnancies complicated with fetal growth restriction

Assisted reproductive technologies do not increase risk of abnormal methylation of PEG1/MEST in human early pregnancy loss

Lentivirus-mediated RNA interference targeting the H19 gene inhibits cell proliferation and apoptosis in human choriocarcinoma cell line JAR

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