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LncRNA pathway involved in premature preterm rupture of membrane (PPROM): an epigenomic approach to study the pathogenesis of reproductive disorders.

ABSTRACT: Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncRNAs were identified with a microarray from placentas of PPROM (group A), which were compared to full-term birth (FTB) (group B), PTB (group C), and premature rupture of membrane (PROM) (group D) at full-term, respectively. Instead of investigating the individual pathogenic role of each lncRNA involved in the molecular mechanism underlying PPROM, we have focused on investigating the metabolic pathways and their functions to explore what is the likely association and how they are possibly involved in the development of PPROM. Six groups, including up-regulation and down-regulation in the comparisons of A vs. B, A vs. C, and A vs. D, of pathways were analyzed. Our results showed that 22 pathways were characterized as up-regulated 7 down-regulated in A vs. C, 18 up-regulated and 15 down-regulated in A vs. D, and 33 up-regulated and 7 down-regulated in A vs. B. Functional analysis showed pathways of infection and inflammatory response, ECM-receptor interactions, apoptosis, actin cytoskeleton, and smooth muscle contraction are the major pathogenic mechanisms involved in the development of PPROM. Characterization of these pathways through identification of lncRNAs opened new avenues for further investigating the epigenomic mechanisms of lncRNAs in PPROM as well as PTB.

SUBMITTER: Luo X

PROVIDER: S-EPMC3842261 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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LncRNA pathway involved in premature preterm rupture of membrane (PPROM): an epigenomic approach to study the pathogenesis of reproductive disorders.

Luo Xiucui X Shi Qingxi Q Gu Yang Y Pan Jing J Hua Maofang M Liu Meilin M Dong Ziqing Z Zhang Meijiao M Wang Leilei L Gu Ying Y Zhong Julia J Zhao Xinliang X Jenkins Edmund C EC Brown W Ted WT Zhong Nanbert N

PloS one 20131127 11

Preterm birth (PTB) is a live birth delivered before 37 weeks of gestation (GW). About one-third of PTBs result from the preterm premature rupture of membranes (PPROM). Up to the present, the pathogenic mechanisms underlying PPROM are not clearly understood. Here, we investigated the differential expression of long chain non-coding RNAs (lncRNAs) in placentas of PTBs with PPROM, and their possible involvement in the pathogenic pathways leading to PPROM. A total number of 1954, 776, and 1050 lncR ...[more]

PMID: 24312190

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Project description:BackgroundPreterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed.MethodsWe developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations.ResultsWe describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene.ConclusionsOur findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.

Project description:A 30-year-old in a second pregnancy presented with new-onset spontaneous vaginal discharge of clear liquid for two hours at a gestational age of 29 weeks + 6 days; no other symptoms were present. Movement aggravated vaginal fluid leakage. She appeared anxious but otherwise vitally stable. An immediate ultrasound scan revealed reduced liquor volume. Conservative management was followed by the surgical delivery of a live preterm neonate. The neonate was admitted to the Special Care Baby Unit and the mother was monitored post-surgically in the obstetric ward. Several studies have described the etiology, pathogenesis, and various approaches to the management of Preterm Prelabour Rupture of Membranes (PPROM); however, there is no single global guideline for managing this condition. There is a consensus that PPROM is a notable risk factor for preterm labor, and significantly impacts both maternal and neonatal morbidity, as well as neonatal mortality. We compared epidemiology across other countries to the statistics obtained from Nigeria as well as management guidelines. Studies have also described the advantages of conservative management over proactive surgical intervention in improving neonatal outcomes. Moreover, the management of PPROM is affected by healthcare resources in different countries and their national protocol, and the impact is significant in developing countries like Nigeria such as the age of fetal viability and the lack of a national protocol. This paper explores PPROM and an uncommon presentation of spontaneous PPROM in the South-South region of Nigeria with only drainage of liquor. This case exemplifies the management approaches of PPROM in an underserved community and the factors that affect the survival of neonates in these communities. The index patient was initially managed conservatively and subsequently delivered a live preterm neonate surgically with good APGAR (appearance, pulse, grimace, activity, and respiration) scores. We expect this case report to prompt a unifying guideline for managing PPROM cases while encouraging advanced research and financial support of PPROM screening and treatment in low-income countries.

Project description:OBJECTIVE: Bacterial colonization of the fetal membranes and its role in pathogenesis of membrane rupture is poorly understood. Prior retrospective work revealed chorion layer thinning in preterm premature rupture of membranes (PPROM) subjects. Our objective was to prospectively examine fetal membrane chorion thinning and to correlate to bacterial presence in PPROM, preterm, and term subjects. STUDY DESIGN: Paired membrane samples (membrane rupture and membrane distant) were prospectively collected from: PPROM?=?14, preterm labor (PTL?=?8), preterm no labor (PTNL?=?8), term labor (TL?=?10), and term no labor (TNL?=?8), subjects. Sections were probed with cytokeratin to identify fetal trophoblast layer of the chorion using immunohistochemistry. Fluorescence in situ hybridization was performed using broad range 16 s ribosomal RNA probe. Images were evaluated, chorion and choriodecidua were measured, and bacterial fluorescence scored. Chorion thinning and bacterial presence were compared among and between groups using Student's t-test, linear mixed effect model, and Poisson regression model (SAS Cary, NC). RESULTS: In all groups, the fetal chorion cellular layer was thinner at rupture compared to distant site (147.2 vs. 253.7 µm, p<0.0001). Further, chorion thinning was greatest among PPROM subjects compared to all other groups combined, regardless of site sampled [PPROM(114.9) vs. PTL(246.0) vs. PTNL(200.8) vs. TL(217.9) vs. TNL(246.5)]. Bacteria counts were highest among PPROM subjects compared to all other groups regardless of site sampled or histologic infection [PPROM(31) vs. PTL(9) vs. PTNL(7) vs. TL(7) vs. TNL(6)]. Among all subjects at both sites, bacterial counts were inversely correlated with chorion thinning, even excluding histologic chorioamnionitis (p<0.0001 and p?=?0.05). CONCLUSIONS: Fetal chorion was uniformly thinner at rupture site compared to distant sites. In PPROM fetal chorion, we demonstrated pronounced global thinning. Although cause or consequence is uncertain, bacterial presence is greatest and inversely correlated with chorion thinning among PPROM subjects.

Dataset Information

LncRNA pathway involved in premature preterm rupture of membrane (PPROM): an epigenomic approach to study the pathogenesis of reproductive disorders.

Publications

LncRNA pathway involved in premature preterm rupture of membrane (PPROM): an epigenomic approach to study the pathogenesis of reproductive disorders.

Similar Datasets

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