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DNA Methylation Profiling of Acute Konwar et al. Epigenetics & Chromatin (2018) 11:63 https://doi.org/10.1186/s13072-018-0234-9 Epigenetics & Chromatin RESEARCH Open Access DNA methylation profling of acute chorioamnionitis‑associated placentas and fetal membranes: insights into epigenetic variation in spontaneous preterm births Chaini Konwar1,2, E. Magda Price1,2,3, Li Qing Wang1,4, Samantha L. Wilson1,2, Jeferson Terry1,5 and Wendy P. Robinson1,2* Abstract Background: Placental infammation, often presenting as acute chorioamnionitis (aCA), is commonly associated with preterm birth. Preterm birth can have both immediate and long-term adverse efects on the health of the baby. Developing biomarkers of infammation in the placenta can help to understand its efects and potentially lead to new approaches for rapid prenatal diagnosis of aCA. We aimed to characterize epigenetic variation associated with aCA in placenta (chorionic villi) and fetal membranes (chorion and amnion) to better understand how aCA may impact processes that lead to preterm birth. This study lays the groundwork for development of novel biomarkers for aCA. Methods: Samples from 44 preterm placentas (chorionic villi) as well as matched chorion and amnion for 16 of these cases were collected for this study. These samples were profled using the Illumina Infnium HumanMethylation850 BeadChip to measure DNA methylation (DNAm) at 866,895 CpGs across the genome. An additional 78 placental sam- ples were utilized to independently validate the array fndings by pyrosequencing. Results: Using a false discovery rate of < 0.15 and average group diference in DNAm of > 0.05, 66 diferentially methylated (DM) CpG sites were identifed between aCA cases and non-aCA cases in chorionic villi. For the majority of these 66 DM CpGs, the DNAm profle of the aCA cases as compared to the non-aCA cases trended in the direc- tion of the blood cell DNAm. Interestingly, neutrophil-specifc DNAm signatures, but not those associated with other immune cell types, were capable of separating aCA cases from the non-aCA cases. Conclusions: Our results suggest that aCA-associated placentas showed altered DNAm signatures that were not observed in the absence of aCA. This DNAm profle is consistent with the activation of the innate immune response in the placenta and/or refect increase in neutrophils as a response to infammation. Keywords: Placenta, Preterm birth, Acute chorioamnionitis, DNA methylation *Correspondence: [email protected] 1 BC Children’s Hospital Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4, Canada Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Konwar et al. Epigenetics & Chromatin (2018) 11:63 Page 2 of 14 Background population studies. Te relationship between DNAm Approximately 15 million children globally (10% of all and gene expression regulation is complex and tends to live births) are born before 37 weeks of gestation and thus be dependent on genomic context [12]. In the context classifed as preterm births (PTB) [1]. Tese babies are of PTB, only a limited number of studies have investi- at an increased risk of life-threatening infections in the gated DNAm changes in the placenta and fetal mem- frst few weeks of life, as well as long-term health com- branes [13–15]. While these studies provided some plications [2, 3]. Preterm births are commonly associated preliminary insights on DNAm patterns associated with infammation of the placenta and fetal membranes with PTB, rarely are the same CpG candidates reported (amnion and chorion) known as chorioamnionitis, esti- as diferentially methylated (DM) between cases and mated to be present in approximately 40% of PTBs [4, 5]. controls. Additionally, the defnition of PTB pathology Chorioamnionitis is also a risk factor for newborn com- was ambiguous, which limits the utility of these stud- plications, regardless of gestational age (GA) at birth [4, ies in understanding the role of DNAm in aCA. A focus 6, 7]. Acute chorioamnionitis (aCA) is characterized by on a distinct pathology linked to PTB, such as aCA, is an infltration of maternal neutrophils through the cho- needed to further research in this area. rioamniotic membranes and into the amniotic space [8]. While DNAm may refect changes to gene expression Tis acute infammation is associated with an increased in specifc cell types, it may also refect altered cell com- risk of fetal infammatory response syndrome (FIRS), position. DNAm signatures difer strikingly between dif- which is life-threatening to the newborn and may often ferent cell lineages, including those in extra-embryonic arise from failure to suppress immune response against tissue. Chorionic villi have a unique DNAm landscape maternal cells that cross the placenta into fetal circula- compared with maternal decidua, fetal membranes tion [8]. Currently, aCA is diagnosed by assessment of (chorion and amnion), and embryonic tissues (brain, clinical signs such as maternal fever, fetal tachycardia, kidney, muscle, spinal cord) [16]. In whole placenta sam- maternal tachycardia, and uterine fundal tenderness. ples (chorionic villi), DNAm patterns also change with Tese clinical signs have variable sensitivity and are non- GA [17], and in certain placental pathologies [16]. We specifc for aCA; thus, a more sensitive and specifc test is hypothesize that the increase in the number of immune needed for earlier and accurate detection of aCA, which cells that occur during placental infammation will be in turn may improve PTB-associated outcomes. refected in changes to DNAm in whole placental sam- Acute chorioamnionitis may be associated with micro- ples. Specifcally, we sought to address three questions: bial invasion of the amniotic space; however, it can also (1) Are there genome-wide DNAm changes associated occur in the absence of detectable microorganisms and with aCA in chorionic villi, chorion and amnion? (2) Are may be triggered by non-microbial “danger signals” there common aCA-associated DNAm changes between including cellular stress and cell death [9, 10]. Te fetus chorionic villi, chorion, and amnion? (3) Can we use also mounts an infammatory response, which together DNAm signatures to characterize immune cell types in with aCA constitutes amniotic fuid infection/infamma- aCA-associated placentas? tion syndrome (AFIS) and associated with changes in the An overview of the study design is presented in Fig. 1. placental and circulating fetal cytokines. Acute chorio- We frst compared genome-wide DNAm profles of aCA- amnionitis is associated with other infammatory lesions associated pregnancy tissues (22 placental chorionic villi, of the placenta including acute intervillositis and villi- including 9 with matched chorion and amnion samples) tis, which afect the chorionic villous trees [7, 11]. Tus, to profles of non-aCA preterm pregnancy tissues (22 characterizing these molecular or cellular changes in the placental chorionic villi, including 7 with matched cho- placenta can in turn improve our current understanding rion and amnion samples). Next, we identifed overlap- of the full consequences of aCA. ping aCA-associated DNAm changes across the three Epigenetics may be a useful tool to characterize some tissue types, chorionic villi, chorion, and amnion. Dif- of the molecular and cellular processes involved in pla- ferentially methylated CpG sites associated with aCA in cental infammation, yet its role in the context of aCA is the “discovery cohort” were followed up in an independ- substantially understudied. Epigenetic infuences refer ent set of samples (N = 42 aCA cases, 36 non-aCA cases) to mitotically heritable chemical modifcations to DNA by a site-specifc technique for measurement of DNAm or the proteins around which DNA is bound that occur (pyrosequencing). Finally, we used unsupervised hier- in the absence of a change to the nucleotide sequence. archical clustering with neutrophil-specifc CpG sites DNA methylation (DNAm), the addition of a methyl to segregate chorionic villus samples based on aCA sta- group to the 5′carbon of cytosine, most typically at tus. Collectively, our genome-wide array analysis of aCA cytosine–phosphate–guanosine (CpG) dinucleotides, placentas was able to capture some immunity-related is a commonly interrogated epigenetic mark in human changes, which may be in part attributable to changes to Konwar et al. Epigenetics & Chromatin (2018) 11:63 Page 3 of 14 Queson: 1 Arethere genome-wideDNAmchanges associated with aCAinchorionic villi, chorionand amnion? Queson: 2 Are there common aCA-associated DNAm changes between chorionic villi, chorion, and amnion Queson: 3 Can we use DNAm signatures to detect immune cell infiltraon in aCA-associated placentas? Discovery cohort Validaon cohort Total n = 44 samples Chorionic villi n = 22 aCa-cases, 22 non-aCA cases Chorion n = 9 aCA-cases, 7 non-aCA cases Amnion n = 9 aCA-cases, 7 non-aCA cases Validaon analysis Array-wideDNAmfindings for3candidateCpGs Illumina Methylaon
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