Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature

Haddad, Ramsi; Tromp, Gerard; Kuivaniemi, Helena; Chaiworapongsa, Tinnakorn; Kim, Yeon Mee; Mazor, Moshe; Romero, Roberto

doi:10.1016/j.ajog.2005.08.057

Cited by 197 publications

(205 citation statements)

References 67 publications

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“…e enrichment of pathways related to ion transport, ion channel activity, and cytokine production among the DMGs between the TNL and TL groups re�ects biochemical and molecular events associated with the onset of labor, which, along with e Scienti�c �orld �ournal 9 hormonal factors, help to initiate parturition. ese results are at least partially in line with previous gene expression pro�ling studies reporting labor-associated cytokine-related gene signatures in human amniotic [36] and chorioamniotic [37] membranes. e overrepresentation of heart-(development and contraction) related gene sets may be explained by the presence of myo�broblasts in the connective tissue of the amnion [38], which have contractile ability [39], and hence are involved in heart rhythm regulation [40] and, possibly, prevention of excessive distension of the amniotic membrane [38].…”

Section: Discussionsupporting

confidence: 81%

Genome-Wide Analysis of DNA Methylation in Human Amnion

Kim¹,

Pitlick²,

Christine³

et al. 2013

Epigenetics and Pathology

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e amnion is a speciali�ed tissue in contact with the amniotic �uid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation pro�ling of human amnion from term (with and without labor) and preterm deliveries. �sing the Illumina In�nium HumanMethylation27 BeadChip, we identi�ed genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisul�te se�uencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing signi�cant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was con�rmed by methylation-speci�c PCR. is work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation pro�les, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.

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Section: Discussionsupporting

confidence: 81%

Genome-Wide Analysis of DNA Methylation in Human Amnion

Kim¹,

Pitlick²,

Christine³

et al. 2013

Epigenetics and Pathology

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“…The expression of these genes, PTGS2, BMP2, NAMPT and CXCL2, increases during fetal membrane activation at labour (Haddad et al 2006, Johnson et al 2006, Mazaki-Tovi et al 2008, Li et al 2011, Lim et al 2012. Their promoters are rich in CpG motifs, which form clusters called CpG islands.…”

Section: Discussionmentioning

confidence: 99%

“…Array-based studies assessing the expression of a large number of genes simultaneously as well as studies determining the expression level of proinflammatory candidate genes have shown that the activity of many inflammatory genes increases at term even in the absence of histological inflammation or detectable infectious insult (Haddad et al 2006, Johnson et al 2006, Mazaki-Tovi et al 2008, Li et al 2011, Lim et al 2012. This changing pattern of gene expression has been described as an 'acute inflammation gene expression signature' (Haddad et al 2006), which transforms the membranes into an activated state producing uterotonic stimulants such as prostaglandins and undergoing structural remodelling in preparation for rupture during labour. The correct timing of inflammatory fetal membrane activation is critical for normal parturition, as pathological inflammation during pregnancy may cause serious complications such as preterm birth (Marvin et al 2002, Shankar et al 2010.…”

Section: Introductionmentioning

confidence: 99%

“…The aim of the present investigation was to explore this possibility by determining the CpG methylation density in the promoters of four inflammatory genes that show increased expression in the fetal membranes and decidua at term labour. These genes encode prostaglandin endoperoxide synthase-2 (PTGS2, the key prostaglandin biosynthetic enzyme), bone morphogenetic protein-2 (BMP2), nicotinamide phosphoribosyltransferase (NAMPT also called PBEF, or visfatin) and chemokine (C-X-C motif) ligand-2 (CXCL2) (Haddad et al 2006, Li et al 2011. We have assessed the methylation status of these genes in amnion collected from normal pregnancies at 11-17 weeks of gestation, at term (37-41 weeks) in the absence of labour and following term labour.…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory and steroid receptor gene methylation in the human amnion and decidua

Mitchell¹,

Sykes²,

Pan³

et al. 2013

Journal of Molecular Endocrinology

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Correct timing of parturition requires inflammatory gene activation in the gestational tissues at term and repression during pregnancy. Promoter methylation at CpG dinucleotides represses gene activity; therefore, we examined the possibility that DNA methylation is involved in the regulation of labour-associated genes in human pregnancy. Amnion and decidua were collected at 11-17 weeks of gestation and at term following elective Caesarean delivery or spontaneous labour. Methylation of the inflammatory genes PTGS2, BMP2, NAMPT and CXCL2 was analysed using the Methyl-Profiler PCR System and bisulphite sequencing. Methylation of the glucocorticoid, progesterone and oestrogen receptor genes, involved in the hormonal regulation of gestational tissue function, and the expression of the DNA methyltransferases DNMT1, -3A and -3B were also determined. Variable proportions of inflammatory and steroid receptor gene copies, to a maximum of 50.9%, were densely methylated in both tissues consistent with repression. Densely methylated copy proportions were significantly different between genes showing no relationship with varying expression during pregnancy, between tissues and in individuals. Methylated copy proportions of all genes in amnion and most genes in decidua were highly correlated in individuals. DNMT1 and -3A were expressed in both tissues with significantly higher levels in the amnion at 11-17 weeks than at term. We conclude that the unmethylated portion of gene copies is responsible for the full range of regulated expression in the amnion and decidua during normal pregnancy. Dense methylation of individually variable gene copy proportions happens in the first trimester amnion influenced by sequence context and affected strongly by individual circumstances.

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“…Labor is recognized as a physiological process of sterile inflammation [1][2][3][4][5], characterized by the infiltration of immune cells into the cervix [6][7][8][9], myometrium [8,[10][11][12], and maternal-fetal interface [8,[13][14][15][16]. This interface includes two areas of contact between the mother and the fetus: the decidua parietalis, which lines the uterine cavity not covered by the placenta and is juxtaposed to the chorion laeve; and the decidua basalis, which lays on the basal plate of the placenta and is invaded by the interstitial trophoblast [16,17].…”

Section: Introductionmentioning

confidence: 99%

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

et al. 2018

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Prior to and during the process of human labor, maternal circulating leukocytes infiltrate the maternal-fetal interface (choriodecidua) and become activated resembling choriodecidual leukocytes. Since, there is no evidence comparing maternal circulating and choriodecidual leukocytes, herein, we characterized their transcriptome and explored the biological processes enriched in choriodecidual leukocytes. From women undergoing spontaneous term labor we isolated circulating and choriodecidual leukocytes, performed microarray analysis (n = 5) and qRT-PCR validation (n = 9) and interaction network analysis with up-regulated genes. We found 270 genes up-regulated and only 17 genes down-regulated in choriodecidual leukocytes compared to maternal circulating leukocytes. The most up-regulated genes were CCL18, GPNMB, SEPP1, FN1, RNASE1, SPP1, C1QC, and PLTP. The biological processes enriched in choriodecidual leukocytes were cell migration and regulation of immune response, chemotaxis, and humoral immune responses. Our results show striking differences between the transcriptome of choriodecidual and maternal circulating leukocytes. Choriodecidual leukocytes are enriched in immune mediators implicated in the spontaneous process of labor at term.

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Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature

Cited by 197 publications

References 67 publications

Genome-Wide Analysis of DNA Methylation in Human Amnion

Genome-Wide Analysis of DNA Methylation in Human Amnion

Inflammatory and steroid receptor gene methylation in the human amnion and decidua

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

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