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Cited by 27

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DNA Methylation of TLR4, VEGFA, and DEFA5 Is Associated With Necrotizing Enterocolitis in Preterm Infants

Klerk, Daphne H., Plösch, Torsten, Verkaik-Schakel, Rikst Nynke, Hulscher, Jan B. F., Kooi, Elisabeth M. W., Bos, Arend F.·2021·Frontiers in Pediatrics
DOI 10.3389/fped.2021.630817
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Abstract

Background: Epigenetic changes, such as DNA methylation, may contribute to an increased susceptibility for developing necrotizing enterocolitis (NEC) in preterm infants. We assessed DNA methylation in five NEC-associated genes, selected from literature: EPO, VEGFA, ENOS, DEFA5, and TLR4 in infants with NEC and controls. Methods: Observational cohort study including 24 preterm infants who developed NEC (≥Bell Stage IIA) and 45 matched controls. DNA was isolated from stool samples and methylation measured using pyrosequencing. We investigated differences in methylation prior to NEC compared with controls. Next, in NEC infants, we investigated methylation patterns long before, a short time before NEC onset, and after NEC. Results: Prior to NEC, only TLR4 CpG 2 methylation was increased in NEC infants (median = 75.4%, IQR = 71.3–83.8%) versus controls (median = 69.0%, IQR = 64.5–77.4%, p = 0.025). In NEC infants, VEGFA CpG 3 methylation was 0.8% long before NEC, increasing to 1.8% a short time before NEC and 2.0% after NEC (p = 0.011; p = 0.021, respectively). A similar pattern was found in DEFA5 CpG 1, which increased from 75.4 to 81.4% and remained 85.3% (p = 0.027; p = 0.019, respectively). These changes were not present for EPO, ENOS, and TLR4. Conclusion: Epigenetic changes of TLR4, VEGFA, and DEFA5 are present in NEC infants and can differ in relation to the time of NEC onset. Differences in DNA methylation of TLR4, VEGFA, and DEFA5 may influence gene expression and increase the risk for developing NEC. This study also demonstrates the use of human DNA extraction from stool samples as a novel non-invasive method for exploring the bowel of preterm infants and which can also be used for necrotizing enterocolitis patients.

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Research works printed but not linked: 42

  1. Lin, 2006, Necrotising enterocolitis, Lancet., 368, 1271, 10.1016/S0140-6736(06)69525-1 · DOI
  2. Heida, 2016, A necrotizing enterocolitis-associated gut microbiota is present in the meconium: results of a prospective study, Clin Infect Dis., 62, 863, 10.1093/cid/ciw016 · DOI
  3. Samuels, 2017, Risk factors for necrotizing enterocolitis in neonates: a systematic review of prognostic studies, BMC Pediatr., 17, 105, 10.1186/s12887-017-0847-3 · DOI
  4. Neu, 2014, Necrotizing enterocolitis: the mystery goes on, Neonatology., 106, 289, 10.1159/000365130 · DOI
  5. Cutfield, 2007, Could epigenetics play a role in the developmental origins of health and disease?, 10.1203/pdr.0b013e318045764c · DOI
  6. Takahashi, 2011, Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells, J Biol Chem., 286, 35755, 10.1074/jbc.M111.271007 · DOI
  7. Merid, 2020, Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age, Genome Med., 12, 25, 10.1186/s13073-020-0716-9 · DOI
  8. Good, 2020, Global hypermethylation of intestinal epithelial cells is a hallmark feature of neonatal surgical necrotizing enterocolitis, Clin Epigenetics, 12, 190, 10.1186/s13148-020-00983-6 · DOI
  9. Gao, 2014, Marked methylation changes in intestinal genes during the perinatal period of preterm neonates, BMC Genomics., 15, 716, 10.1186/1471-2164-15-716 · DOI
  10. Ng, 2015, Comparative MiRNA expressional profiles and molecular networks in human small bowel tissues of necrotizing enterocolitis and spontaneous intestinal perforation, PLoS ONE., 10, e0135737, 10.1371/journal.pone.0135737 · DOI
  11. Shiou, 2011, Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis, J Biol Chem., 286, 12123, 10.1074/jbc.M110.154625 · DOI
  12. Sullivan, 2010, An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products, J Pediatr., 156, 562, 10.1016/j.jpeds.2009.10.040 · DOI
  13. Bowker, 2018, Intestinal microcirculation and necrotizing enterocolitis: the vascular endothelial growth factor system, Semin Fetal Neonatal Med., 23, 411, 10.1016/j.siny.2018.08.008 · DOI
  14. Sabnis, 2015, Intestinal vascular endothelial growth factor is decreased in necrotizing enterocolitis, Neonatology., 107, 191, 10.1159/000368879 · DOI
  15. Cuna, 2017, Genetic alterations in necrotizing enterocolitis, Semin Perinatol., 41, 61, 10.1053/j.semperi.2016.09.019 · DOI
  16. Nowicki, 2007, Endothelial nitric oxide synthase in human intestine resected for necrotizing enterocolitis, J Pediatr., 150, 40, 10.1016/j.jpeds.2006.09.029 · DOI
  17. Underwood, 2012, Paneth cells and necrotizing enterocolitis, Gut Microbes, 3, 562, 10.4161/gmic.21738 · DOI
  18. Hackam, 2018, Toll-Like Receptor-Mediated Intestinal Inflammatory Imbalance in the Pathogenesis of Necrotizing Enterocolitis, Cell Mol Gastroenterol Hepatol., 6, 229, 10.1016/j.jcmgh.2018.04.001 · DOI
  19. Sodhi, 2012, Intestinal epithelial Toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice, Gastroenterology, 143, 708, 10.1053/j.gastro.2012.05.053 · DOI
  20. Lu, 2008, LPS/TLR4 signal transduction pathway, Cytokine., 42, 145, 10.1016/j.cyto.2008.01.006 · DOI · Paper page
  21. De, 2015, Early detection of necrotizing enterocolitis by fecal volatile organic compounds analysis, J Pediatr., 167, 562, 10.1016/j.jpeds.2015.05.044 · DOI
  22. van, 2009, Stem cells, self-renewal, and differentiation in the intestinal epithelium, Annu Rev Physiol., 71, 241, 10.1146/annurev.physiol.010908.163145 · DOI
  23. Chapkin, 2010, Noninvasive stool-based detection of infant gastrointestinal development using gene expression profiles from exfoliated epithelial cells, Am J Physiol Gastrointest Liver Physiol., 298, G582, 10.1152/ajpgi.00004.2010 · DOI
  24. Chandel, 2011, Live colonocytes in newborn stool: surrogates for evaluation of gut physiology and disease pathogenesis, Pediatr Res., 70, 153, 10.1203/PDR.0b013e3182225ac9 · DOI
  25. Stinson, 2018, Comparison of meconium DNA extraction methods for use in microbiome studies, Front Microbiol., 9, 270, 10.3389/fmicb.2018.00270 · DOI
  26. Steinmann, 2011, Epigenetic silencing of erythropoietin in human cancers, Genes Cancer., 2, 65, 10.1177/1947601911405043 · DOI
  27. Sundrani, 2013, Differential placental methylation and expression of VEGF, FLT-1 and KDR genes in human term and preterm preeclampsia, Clin Epigenetics., 5, 6, 10.1186/1868-7083-5-6 · DOI
  28. Karantzoulis-Fegaras, 1999, Characterization of the human endothelial nitric-oxide synthase promoter, J Biol Chem, 274, 3076, 10.1074/jbc.274.5.3076 · DOI
  29. Kheirandish-Gozal, 2013, Endothelial dysfunction in children with obstructive sleep apnea is associated with epigenetic changes in the eNOS gene, Chest., 143, 971, 10.1378/chest.12-2026 · DOI
  30. Cerrillo, 2018, Alpha-defensins (α-Defs) in Crohn's disease: decrease of ileal α-Def 5 via permanent methylation and increase in plasma α-Def 1-3 concentrations offering biomarker utility, Clin Exp Immunol., 192, 120, 10.1111/cei.13085 · DOI
  31. Kim, 2016, Epigenetic modification of TLR4 promotes activation of NF-κB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer, Oncotarget., 7, 4195, 10.18632/oncotarget.6549 · DOI
  32. Du, 2019, RFX1 downregulation contributes to TLR4 overexpression in CD14+ monocytes via epigenetic mechanisms in coronary artery disease, Clin Epigenetics., 11, 44, 10.1186/s13148-019-0646-9 · DOI
  33. Hoftiezer, 2019, From population reference to national standard: new and improved birthweight charts, Am J Obstet Gynecol., 220, 383, 10.1016/j.ajog.2018.12.023 · DOI
  34. Leaphart, 2007, A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair, J Immunol., 179, 4808, 10.4049/jimmunol.179.7.4808 · DOI
  35. Meng, 2015, Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis, Pediatr Res., 77, 416, 10.1038/pr.2014.207 · DOI
  36. Hackam, 2013, Mechanisms of gut barrier failure in the pathogenesis of necrotizing enterocolitis: toll-like receptors throw the switch, Semin Pediatr Surg., 22, 76, 10.1053/j.sempedsurg.2013.01.003 · DOI
  37. Siddique, 2013, Targeted methylation and gene silencing of VEGF-A in human cells by using a designed Dnmt3a–Dnmt3L single-chain fusion protein with increased DNA methylation activity, J Mol Biol, 425, 479, 10.1016/j.jmb.2012.11.038 · DOI
  38. Heida, 2016, Paneth cells in the developing gut: when do they arise and when are they immune competent?, Pediatr Res., 80, 306, 10.1038/pr.2016.67 · DOI
  39. McElroy, 2013, Paneth cells and necrotizing enterocolitis: a novel hypothesis for disease pathogenesis, Neonatology., 103, 10, 10.1159/000342340 · DOI
  40. Choudhry, 2018, Advances in hypoxia-inducible factor biology, Cell Metab., 27, 281, 10.1016/j.cmet.2017.10.005 · DOI
  41. Lueschow, 2018, Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis, PLoS ONE., 13, e0204967, 10.1371/journal.pone.0204967 · DOI
  42. Heida, 2017, Increased incidence of necrotizing enterocolitis in the Netherlands after implementation of the new Dutch guideline for active treatment in extremely preterm infants: results from three academic referral centers, J Pediatr Surg., 52, 273, 10.1016/j.jpedsurg.2016.11.024 · DOI

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Metadata

Authors
Klerk, D. H., Plösch, T., Verkaik-Schakel, R. N., Hulscher, J. B. F., Kooi, E. M. W., & Bos, A. F.
Venue
Frontiers in Pediatrics
Publisher
Frontiers Media SA
Published
2021-03-04
Volume
9
ISSN
2296-2360
DOI
10.3389/fped.2021.630817
Cited by
27
References
1
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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CoChat. (2026). Citation check: DNA Methylation of TLR4, VEGFA, and DEFA5 Is Associated With Necrotizing Enterocolitis in Preterm Infants. https://app.cochat.ai/papers/10.3389/fped.2021.630817
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Klerk, D. H., Plösch, T., Verkaik-Schakel, R. N., Hulscher, J. B. F., Kooi, E. M. W., & Bos, A. F. (2021). DNA Methylation of TLR4, VEGFA, and DEFA5 Is Associated With Necrotizing Enterocolitis in Preterm Infants. Frontiers in Pediatrics. https://doi.org/10.3389/fped.2021.630817

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