Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice

Kanayama, Naohiro; Takahashi, K.; Matsuura, Toshiki; Sugimura, Motoi; Kobayashi, Takao; Moniwa, Nobuhiko; Tomita, Motowo; Nakayama, Keiko

doi:10.1093/molehr/8.12.1129

Cited by 133 publications

(95 citation statements)

References 43 publications

(58 reference statements)

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“…Both hyper-and hypoplastic placentation are linked to imprinted gene function (Kanayama et al, 2002;Murdoch et al, 2006; reviewed in Kaneko-Ishino et al, 2003). The most dramatic example of this is diploid, uniparental embryos.…”

Section: Results and Discusssionmentioning

confidence: 99%

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

Kuzmin

Han

Golding

et al. 2008

Gene Expression Patterns

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Genomic imprinting has dramatic effects on placental development, as has been clearly observed in interspecific hybrid, somatic cell nuclear transfer, and uniparental embryos. In fact, the earliest defects in uniparental embryos are evident first in the extraembryonic trophoblast. We performed a microarray comparison of gynogenetic and androgenetic mouse blastocysts, which are predisposed to placental pathologies, to identify imprinted genes. In addition to identifying a large number of known imprinted genes, we discovered that the Polycomb group (PcG) gene Sfmbt2 is imprinted. Sfmbt2 is expressed preferentially from the paternal allele in early embryos, and in later stage extraembryonic tissues. A CpG island spanning the transcriptional start site is differentially methylated on the maternal allele in e14.5 placenta. Sfmbt2 is located on proximal chromosome 2, in a region known to be imprinted, but for which no genes had been identified until now. This possibly identifies a new imprinted domain within the murine genome. We further demonstrate that murine SFMBT2 protein interacts with the transcription factor YY1, similar to the Drosophila PHO-RC. KeywordsGenomic Imprinting; Sfmbt2; PcG gene; Extraembryonic tissues; placenta; MMU2; YY1; microarrays; uniparental embryos Results and DiscusssionThe role played by imprinted genes in placental development is gaining wider attention as the impact of imprinting disruptions on placental pathology is explored. Both hyper-and hypoplastic placentation are linked to imprinted gene function (Kanayama et al., 2002;Murdoch et al., 2006; reviewed in Kaneko-Ishino et al., 2003). The most dramatic example of this is diploid, uniparental embryos. Gynogenetic embryos (two maternal/no paternal genomes) and androgenetic embryos (two paternal/no maternal genomes) both exhibit defects in the earliest differentiated tissue in mammals, the extraembryonic trophoblast (Barton et al., 1984;McGrath and Solter, 1984;Mann, 2005). At mid-gestation, gynogenetic embryos possess only a few residual trophoblast giant cells while androgenetic embryos are characterized by a mass of hypertrophic trophoblast. These observations indicate that a suite of genes required * Corresponding author. s.varmuza@utoronto.ca; tel. 1-416-978-2759; FAX 1-416-978-8532. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptGene Expr Patterns. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Gene Expr Patterns. 2008 January ; 8(2): 107-116. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manu...

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Section: Results and Discusssionmentioning

confidence: 99%

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

Kuzmin

Han

Golding

et al. 2008

Gene Expression Patterns

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“…These mainly included the single nucleotide polymorphorism of the STOX1 gene (van Dijk et al) 15 and the gene mutation of the parentally imprinted p57 gene (Kanayama et al) 16 The paternally imprinted H19 gene is transcribed as an untranslated RNA that may serve as a riboregulator. The gene is located in close proximity to the maternally imprinted IGF-2 gene on chromosome 11p15.5.…”

Section: Introductionmentioning

confidence: 99%

Detection of global DNA methylation and paternally imprinted H19 gene methylation in preeclamptic placentas

et al. 2011

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Preeclampsia (PE) is a severe hypertensive disorder associated with pregnancy; despite substantial research effort in the past several years, the etiology of PE is still unclear. The role of epigenetic factors in the etiology of PE, including DNA methylation, has been poorly characterized. In the present study, we investigated global DNA methylation as well as DNA methylation of the paternally imprinted H19 gene in preeclamptic placentas. Using 5-methylcytosine immunohistochemistry and Alu and LINE-1 repeat pyrosequencing, we found that the global DNA methylation level and the DNA (cytosine-5) methyltransferase 1 mRNA level were significantly higher in the early-onset preeclamptic placentas when compared with the normal controls. Data from methylation-sensitive high resolution melting demonstrated hypermethylation of the promoter region of the H19 gene, and results of real-time PCR showed decreased mRNA expression of H19 gene in the early-onset preeclamptic placentas as compared with the normal controls. Our results suggest that abnormal DNA methylation during placentation might be involved in the pathophysiology of PE, especially early-onset preeclampsia.

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“…Further support for this hypothesis comes from the variety of mechanisms resulting in PE-like symptoms in mouse models. PE mouse models have been generated genetically from spontaneous hypertensive mice (5), by excessive angiotensin pathway activation (6), and by mutations affecting trophoblast cell cycle regulation (7). Interestingly, the anti-angiogenic factor, sFLT1, is present in elevated levels in the maternal circulation in most human PE pregnancies, but not all (8), and in some mouse models of PE (e.g.…”

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confidence: 99%

Translational Analysis of Mouse and Human Placental Protein and mRNA Reveals Distinct Molecular Pathologies in Human Preeclampsia

Cox

Sharma

Evangelou

et al. 2011

Molecular & Cellular Proteomics

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Preeclampsia (PE) adversely impacts ϳ5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar

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Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice

Cited by 133 publications

References 43 publications

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

Detection of global DNA methylation and paternally imprinted H19 gene methylation in preeclamptic placentas

Translational Analysis of Mouse and Human Placental Protein and mRNA Reveals Distinct Molecular Pathologies in Human Preeclampsia

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