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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2019

Open Access 01-12-2019 | Premature Birth | Research article

Effect of prematurity on genome wide methylation in the placenta

Authors: Jessica Schuster, Alper Uzun, Joan Stablia, Christoph Schorl, Mari Mori, James F. Padbury

Published in: BMC Medical Genetics | Issue 1/2019

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Abstract

Background

Preterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The “fetal origins” hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs).

Results

Enrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth.

Conclusion

These studies form the basis for future studies on the epigenetics of preterm birth, “fetal programming” and the impact of environment exposures on this important clinical challenge.
Appendix
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Literature
1.
2.
Kerkhof GF, Willemsen RH, Leunissen RW, Breukhoven PE, Hokken-Koelega AC. Health profile of young adults born preterm: negative effects of rapid weight gain in early life. J Clin Endocrinol Metab. 2012;97(12):4498–506.PubMedCrossRef
3.
Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med. 2008;359(1):61–73.PubMedPubMedCentralCrossRef
4.
5.
Suter MA, Aagaard-Tillery KM. Environmental influences on epigenetic profiles. Semin Reprod Med. 2009;27(5):380–90.PubMedCrossRef
6.
7.
Ginder GD, Gnanapragasam MN, Mian OY. The role of the epigenetic signal, DNA methylation, in gene regulation during erythroid development. Curr Top Dev Biol. 2008;82:85–116.PubMedCrossRef
8.
Mikheev AM, Nabekura T, Kaddoumi A, Bammler TK, Govindarajan R, Hebert MF, et al. Profiling gene expression in human placentae of different gestational ages: an OPRU network and UW SCOR study. Reprod Sci. 2008;15(9):866–77.PubMedPubMedCentralCrossRef
9.
Winn VD, Haimov-Kochman R, Paquet AC, Yang YJ, Madhusudhan MS, Gormley M, et al. Gene expression profiling of the human maternal-fetal interface reveals dramatic changes between midgestation and term. Endocrinology. 2007;148(3):1059–79.PubMedCrossRef
10.
Parets SE, Conneely KN, Kilaru V, Fortunato SJ, Syed TA, Saade G, et al. Fetal DNA methylation associates with early spontaneous preterm birth and gestational age. PLoS One. 2013;8(6):e67489.PubMedPubMedCentralCrossRef
11.
Schroeder JW, Conneely KN, Cubells JC, Kilaru V, Newport DJ, Knight BT, et al. Neonatal DNA methylation patterns associate with gestational age. Epigenetics. 2011;6(12):1498–504.PubMedPubMedCentralCrossRef
12.
Novakovic B, Yuen RK, Gordon L, Penaherrera MS, Sharkey A, Moffett A, et al. Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors. BMC Genomics. 2011;12:529.PubMedPubMedCentralCrossRef
13.
Maccani JZ, Koestler DC, Houseman EA, Marsit CJ, Kelsey KT. Placental DNA methylation alterations associated with maternal tobacco smoking at the RUNX3 gene are also associated with gestational age. Epigenomics. 2013;5(6):619–30.PubMedPubMedCentralCrossRef
14.
Chavan-Gautam P, Sundrani D, Pisal H, Nimbargi V, Mehendale S, Joshi S. Gestation-dependent changes in human placental global DNA methylation levels. Mol Reprod Dev. 2011;78(3):150.PubMedCrossRef
15.
Yuen RK, Penaherrera MS, von Dadelszen P, McFadden DE, Robinson WP. DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia. Eur J Hum Genet. 2010;18(9):1006–12.PubMedPubMedCentralCrossRef
16.
Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 2009;5(8):e1000602.PubMedPubMedCentralCrossRef
17.
Marsit CJ, Lambertini L, Maccani MA, Koestler DC, Houseman EA, Padbury JF, et al. Placenta-imprinted gene expression association of infant neurobehavior. J Pediatr. 2012;160(5):854–60 e2.PubMedCrossRef
18.
Zhao MT, Whyte JJ, Hopkins GM, Kirk MD, Prather RS. Methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) using low amounts of genomic DNA. Cell Reprogram. 2014;16(3):175–84.PubMedCrossRef
19.
Yu G, Wang LG, He QY. ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics. 2015;31(14):2382–3.PubMedCrossRef
20.
Chim SS, Lee WS, Ting YH, Chan OK, Lee SW, Leung TY. Systematic identification of spontaneous preterm birth-associated RNA transcripts in maternal plasma. PLoS One. 2012;7(4):e34328.PubMedPubMedCentralCrossRef
21.
22.
Lynch VJ, Leclerc RD, May G, Wagner GP. Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nat Genet. 2011;43(11):1154–9.PubMedCrossRef
23.
Engel SM, Joubert BR, Wu MC, Olshan AF, Haberg SE, Ueland PM, et al. Neonatal genome-wide methylation patterns in relation to birth weight in the Norwegian mother and child cohort. Am J Epidemiol. 2014;179(7):834–42.PubMedPubMedCentralCrossRef
24.
Teh AL, Pan H, Chen L, Ong ML, Dogra S, Wong J, et al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes. Genome Res. 2014;24(7):1064–74.PubMedPubMedCentralCrossRef
25.
Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–92.PubMedCrossRef
26.
Daura-Oller E, Cabre M, Montero MA, Paternain JL, Romeu A. Specific gene hypomethylation and cancer: new insights into coding region feature trends. Bioinformation. 2009;3(8):340–3.PubMedPubMedCentralCrossRef
27.
Conrad KP, Joffe GM, Kruszyna H, Kruszyna R, Rochelle LG, Smith RP, et al. Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J. 1993;7(6):566–71.PubMedCrossRef
28.
Myatt L, Brewer A, Brockman DE. The action of nitric oxide in the perfused human fetal-placental circulation. Am J Obstet Gynecol. 1991;164(2):687–92.PubMedCrossRef
29.
Bielecki M, Tomasiak M, Jarocki S, Bodzenta-Lukaszyk A, Bielecki DA, Zdrodowska J. Nitric oxide in preterm labor. Ginekol Pol. 2003;74(5):339–44.PubMed
30.
Hsu CD, Meaddough E, Aversa K, Hong SF, Lee IS, Bahodo-Singh RO, et al. Dual roles of amniotic fluid nitric oxide and prostaglandin E2 in preterm labor with intra-amniotic infection. Am J Perinatol. 1998;15(12):683–7.PubMedCrossRef
31.
Chwalisz K, Garfield RE. Role of nitric oxide in the uterus and cervix: implications for the management of labor. J Perinat Med. 1998;26(6):448–57.PubMedCrossRef
32.
Al-Hijji J, Andolf E, Laurini R, Batra S. Nitric oxide synthase activity in human trophoblast, term placenta and pregnant myometrium. Reprod Biol Endocrinol. 2003;1:51.PubMedPubMedCentralCrossRef
33.
Saji F, Koyama M, Matsuzaki N. Current topic: human placental fc receptors. Placenta. 1994;15(5):453–66.PubMedCrossRef
34.
Ozdemir O, Dinleyici EC, Tekin N, Colak O, Aksit MA. Low-mannose-binding lectin levels in susceptibility to neonatal sepsis in preterm neonates with fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2010;23(9):1009–13.PubMedCrossRef
35.
Malhotra R, Willis AC, Lopez Bernal A, Thiel S, Sim RB. Mannan-binding protein levels in human amniotic fluid during gestation and its interaction with collectin receptor from amnion cells. Immunology. 1994;82(3):439–44.PubMedPubMedCentral
36.
Petersen SV, Thiel S, Jensen L, Vorup-Jensen T, Koch C, Jensenius JC. Control of the classical and the MBL pathway of complement activation. Mol Immunol. 2000;37(14):803–11.PubMedCrossRef
37.
Gibson CS, Maclennan AH, Haan EA, Priest K, Dekker GA. Fetal MBL2 haplotypes combined with viral exposure are associated with adverse pregnancy outcomes. J Matern Fetal Neonatal Med. 2011;24(6):847–54.PubMedCrossRef
38.
Allen LH. Anemia and iron deficiency: effects on pregnancy outcome. Am J Clin Nutr. 2000;71(5 Suppl):1280S–4S.PubMedCrossRef
39.
Mando C, Tabano S, Colapietro P, Pileri P, Colleoni F, Avagliano L, et al. Transferrin receptor gene and protein expression and localization in human IUGR and normal term placentas. Placenta. 2011;32(1):44–50.PubMedCrossRef
40.
41.
Clark C, Palta P, Joyce CJ, Scott C, Grundberg E, Deloukas P, et al. A comparison of the whole genome approach of MeDIP-seq to the targeted approach of the Infinium HumanMethylation450 BeadChip((R)) for methylome profiling. PLoS One. 2012;7(11):e50233.PubMedPubMedCentralCrossRef
42.
Wadhwa PD, Buss C, Entringer S, Swanson JM. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med. 2009;27(5):358–68.PubMedPubMedCentralCrossRef
43.
Ponder KL, Salisbury A, McGonnigal B, Laliberte A, Lester B, Padbury JF. Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming. Dev Psychobiol. 2011;53(7):711–23.PubMedPubMedCentralCrossRef
44.
Wolfe LM, Thiagarajan RD, Boscolo F, Tache V, Coleman RL, Kim J, et al. Banking placental tissue: an optimized collection procedure for genome-wide analysis of nucleic acids. Placenta. 2014;35(8):645–54.PubMedPubMedCentralCrossRef
45.
46.
47.
48.
49.
Meyer LR, Zweig AS, Hinrichs AS, Karolchik D, Kuhn RM, Wong M, et al. The UCSC genome browser database: extensions and updates 2013. Nucleic Acids Res. 2013;41(Database issue):D64–9.PubMed
50.
Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–30.CrossRef
51.
Zhang B, Xing X, Li J, Lowdon RF, Zhou Y, Lin N, et al. Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers. BMC Genomics. 2014;15:868.PubMedPubMedCentralCrossRef
Metadata
Title
Effect of prematurity on genome wide methylation in the placenta
Authors
Jessica Schuster
Alper Uzun
Joan Stablia
Christoph Schorl
Mari Mori
James F. Padbury
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2019
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-019-0835-6

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