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Maternal Pregravid Obesity Remodels the DNA Methylation Landscape Of Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program This information is current as of September 26, 2021. Suhas Sureshchandra, Randall M. Wilson, Maham Rais, Nicole E. Marshall, Jonathan Q. Purnell, Kent L. Thornburg and Ilhem Messaoudi J Immunol published online 8 September 2017 http://www.jimmunol.org/content/early/2017/09/07/jimmun Downloaded from ol.1700434 Supplementary http://www.jimmunol.org/content/suppl/2017/09/08/jimmunol.170043 http://www.jimmunol.org/ Material 4.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 8, 2017, doi:10.4049/jimmunol.1700434 The Journal of Immunology Maternal Pregravid Obesity Remodels the DNA Methylation Landscape of Cord Blood Monocytes Disrupting Their Inflammatory Program Suhas Sureshchandra,* Randall M. Wilson,† Maham Rais,† Nicole E. Marshall,‡ Jonathan Q. Purnell,x Kent L. Thornburg,x and Ilhem Messaoudi* Prepregnancy maternal obesity is associated with adverse outcomes for the offspring, including increased incidence of neonatal bacterial sepsis and necrotizing enterocolitis. We recently reported that umbilical cord blood (UCB) monocytes from babies born to obese mothers generate a reduced IL-6/TNF-a response to TLR 1/2 and 4 ligands compared to those collected from lean mothers. These observations suggest altered development of the offspring’s immune system, which in turn results in dysregulated function. We therefore investigated transcriptional and epigenetic differences within UCB monocytes stratified by prepregnancy Downloaded from maternal body mass index. We show that UCB monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared with those born to lean mothers, at the level of secreted immune mediators and transcription. Because gene expression profiles of resting UCB monocytes from both groups were comparable, we next investigated the role of epigenetic differences. Indeed, we detected stark differences in methylation levels within promoters and regulatory regions of genes involved in TLR signaling in resting UCB monocytes. Interestingly, the DNA methylation status of resting cells was highly predictive of transcriptional changes post-LPS stimulation, suggesting that cytosine methylation is one of the dominant mechanisms driving http://www.jimmunol.org/ functional inadequacy in UCB monocytes obtained from babies born to obese mothers. These data highlight a potentially critical role of maternal pregravid obesity-associated epigenetic changes in influencing the function of an offspring’s monocytes at birth. These findings further our understanding of mechanisms that explain the increased risk of infection in neonates born to mothers with high prepregnancy body mass index. The Journal of Immunology, 2017, 199: 000–000. lmost 37% of women of childbearing age are categorized obesity include increased rates of preeclampsia, gestational hyper- as obese, making obesity one of the most common tension, gestational diabetes, placental abruption, preterm delivery, comorbidities during pregnancy (1). It is well estab- and cesarean delivery (1). For the fetus, complications include A by guest on September 26, 2021 lished that a high prepregnancy (pregravid) body mass index increased risk of stillbirth, abnormal growth, and cardiac or neural (BMI) is associated with detrimental health outcomes for both tube defects (1, 4). Moreover, neonates born to obese mothers are mother and child (2–4). Maternal complications of pregravid at increased risk of bacterial sepsis and necrotizing enterocolitis, requiring admission to the neonatal intensive care unit (5, 6). *Department of Molecular Biology and Biochemistry, School of Biological Sciences, Some adverse health outcomes for the offspring persist into University of California Irvine, Irvine, CA 92697; †Division of Biomedical Sciences, Uni- adulthood, including increased susceptibility to respiratory in- versity of California Riverside, Riverside, CA 92521; ‡Maternal-Fetal Medicine, x fections such as respiratory syncytial virus (7, 8), asthma (9), Oregon Health and Science University, Portland, OR 97239; and Department of Medicine, The Knight Cardiovascular Institute, Oregon Health and Science Uni- wheezing (10), cancer (11), type 2 diabetes (12), and cardiovas- versity, Portland, OR 97239 cular disease (13), culminating in an increased risk for all-cause ORCIDs: 0000-0003-2555-2111 (M.R.); 0000-0003-3105-555X (N.E.M.). offspring mortality (14). Received for publication March 24, 2017. Accepted for publication August 7, 2017. The aforementioned observations strongly suggest that pregravid This work was supported by National Institutes of Health Grants KL2TR000152 (to obesity disrupts the development and maturation of the offspring’s N.E.M.) and R03AI112808 (to I.M.) and the National Center for Advancing Trans- immune system in utero. This hypothesis is supported by studies lational Sciences of the National Institutes of Health under Award UL1TR000128. in murine models that have shown detrimental effects on the Gene expression and methylation data have been submitted to the National Center for Biotechnology Information Sequence Read Archive (http://www.ncbi.nlm.nih.gov/ immune system of pups born to obese compared with lean dams sra) under accession number PRJNA398556. (15, 16). Specifically, pups born to obese dams generated disparate S.S., N.E.M., J.Q.P., K.L.T., and I.M. conceived and designed the experiments; S.S., IgG (smaller) and IgE (larger) Ab responses following vaccination R.M.W., and M.R. performed the experiments; S.S. and R.M.W. analyzed the data; with OVA (15). If these results are true in humans, they could S.S. and I.M. wrote the paper with input from N.E.M., J.Q.P., and K.L.T. explain the increased incidence of asthma (9) and wheezing (10) Address correspondence and reprint requests to Dr. Ilhem Messaoudi, 2400 Biolog- ical Sciences III, University of California Irvine, Irvine, CA 92697-3900. E-mail in children born to obese mothers. Additional rodent studies address: [email protected] reported greater morbidity and mortality following bacterial The online version of this article contains supplemental material. infection (Escherichia coli sepsis and methicillin-resistant Staphy- Abbreviations used in this article: BMI, body mass index; DEG, differentially expressed lococcus aureus infection) and greater susceptibility to auto- gene; DMC, differentially methylated cytosine; DMR, differentially methylated region; immune encephalitis in pups born to obese dams (16). Lastly, ex eDMR, empirical DMR; FC, fold change; FDR, false discovery rate; GO, gene ontology; RPKM, read per kilobase of transcript per million mapped reads; TF, tran- vivo LPS stimulation of colonic lamina propria lymphocytes scription factor; TSS, transcription start site; UCB, umbilical cord blood; UCBMC, resulted in increased secretion of inflammatory cytokines IL-6, UCB mononuclear cell. IL-1b, and IL-17, whereas LPS stimulation of splenocytes resulted Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 in decreased levels of TNF-a and IL-6 in pups born to obese dams www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700434 2 EPIGENETIC IMPACT OF MATERNAL OBESITY ON CORD BLOOD MONOCYTE (16). Collectively, these data strongly suggest dysregulated im- Abs conjugated to magnetic microbeads per the manufacturer’s recom- munity in pups born to obese dams where aberrant responses (such mendations (Miltenyi Biotec, San Diego, CA). Magnetically bound UCB as to auto-antigens) are exaggerated, whereas protective anti- monocytes were washed and eluted for collection. Positive selection of UCB monocytes was chosen to ensure high purity of the population, microbial responses are reduced. Similarly, a baboon study which was assessed using flow cytometry and was $90% for all samples reported significant changes in the expression of genes involved in analyzed. Ag presentation, complement and coagulation cascade, leukocyte LPS stimulation and detection of soluble mediators migration, and BCR signaling in PBMCs collected from infants born to obese compared with lean dams (17). Purified UCB monocytes were plated at 2 3 105 per well and stimulated However, only a few studies have explored the impact of ma- with 100 ng (1 mg/ml) of LPS (TLR4 ligand, E. coli 055:B5; InvivoGen, ternal pregravid obesity on neonatal immune function in humans. San Diego, CA) or left untreated for 16 h at 37˚C and 5% CO2. The above concentration of LPS was previously standardized for robust detection of One study reported that children born to obese mothers have a 16- gene expression in primary human monocytes
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