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The idiopathic preterm delivery methylation profile in umbilical cord blood DNA.

ABSTRACT: Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05.The analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery. 1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p?

SUBMITTER: Fernando F

PROVIDER: S-EPMC4588235 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The idiopathic preterm delivery methylation profile in umbilical cord blood DNA.

Fernando Febilla F Keijser Remco R Henneman Peter P van der Kevie-Kersemaekers Anne-Marie F AM Mannens Marcel Mam MM van der Post Joris Am JA Afink Gijs B GB Ris-Stalpers Carrie C

BMC genomics 20150929

<h4>Background</h4>Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, ...[more]

PMID: 26419829

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Project description:BackgroundPremature infants are highly vulnerable to infection. This is partly attributable to the preterm immune system, which differs from that of the term neonate in cell composition and function. Multiple studies have found differential DNA methylation (DNAm) between preterm and term infants' cord blood; however, interpretation of these studies is limited by the confounding factor of blood cell composition. This study evaluates the epigenetic impact of preterm birth in isolated hematopoietic cell populations, reducing the concern of cell composition differences.MethodsGenome-wide DNAm was measured using the Illumina 450K array in T cells, monocytes, granulocytes, and nucleated red blood cells (nRBCs) isolated from cord blood of 5 term and 5 preterm (<31 weeks gestational age) newborns. DNAm of hematopoietic cells was compared globally across the 450K array and through site-specific linear modeling.ResultsNucleated red blood cells (nRBCs) showed the most extensive changes in DNAm, with 9258 differentially methylated (DM) sites (FDR < 5%, |Δβ| > 0.10) discovered between preterm and term infants compared to the <1000 prematurity-DM sites identified in white blood cell populations. The direction of DNAm change with gestational age at these prematurity-DM sites followed known patterns of hematopoietic differentiation, suggesting that term hematopoietic cell populations are more epigenetically mature than their preterm counterparts. Consistent shifts in DNAm between preterm and term cells were observed at 25 CpG sites, with many of these sites located in genes involved in growth and proliferation, hematopoietic lineage commitment, and the cytoskeleton. DNAm in preterm and term hematopoietic cells conformed to previously identified DNAm signatures of fetal liver and bone marrow, respectively.ConclusionsThis study presents the first genome-wide mapping of epigenetic differences in hematopoietic cells across the late gestational period. DNAm differences in hematopoietic cells between term and <31 weeks were consistent with the hematopoietic origin of these cells during ontogeny, reflecting an important role of DNAm in their regulation. Due to the limited sample size and the high coincidence of prematurity and multiple births, the relationship between cause of preterm birth and DNAm could not be evaluated. These findings highlight gene regulatory mechanisms at both cell-specific and systemic levels that may be involved in fetal immune system maturation.

Project description:BACKGROUND:The etiology and mechanism of spontaneous preterm birth (sPTB) are still unclear. Accumulating evidence has documented that various environmental exposure scenarios may cause maternal and fetal epigenetic changes, which initiates the focus on whether epigenetics can contribute to the occurrence of sPTB. Therefore, we conducted the current study to examine and compare the DNA methylation changes associated with sPTB in placenta and cord blood. METHODS:This hospital-based case-control study was carried out at three Women and Children's hospitals in South China, where 32 spontaneous preterm births and 16 term births were recruited. Genome-wide DNA methylation profiles of the placenta and cord blood from these subjects were measured using the Illumina HumanMethylation EPIC BeadChip, and sPTB-associated differential methylated CpG sites were identified using limma regression model, after controlling for major maternal and infant confounders. Further Gene Ontology analysis was performed with PANTHER in order to assess different functional enrichment of the sPTB-associated genes in placenta and cord blood. RESULTS:After controlling for potential confounding factors, one differentially methylated position (DMP) in placenta and 31 DMPs in cord blood were found significantly associated with sPTB (Bonferroni corrected p < 0.05). The sPTB-associated CpG sites in placenta were mapped to genes that showed higher enrichment on biological processes including biological regulation, multicellular organismal process, and especially response to stimulus, while those in cord blood were mapped to genes that had higher enrichment on biological processes concerning cellular process, localization, and particularly metabolic process. CONCLUSION:Findings of this study indicated that DNA methylation alteration in both placenta and cord blood are associated with sPTB, yet the DNA methylation modification patterns may appear differently in placenta and cord blood.

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The idiopathic preterm delivery methylation profile in umbilical cord blood DNA.

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The idiopathic preterm delivery methylation profile in umbilical cord blood DNA.

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