Global hypermethylation of intestinal epithelial cells is a hallmark feature of neonatal surgical necrotizing enterocoli
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RESEARCH
Global hypermethylation of intestinal epithelial cells is a hallmark feature of neonatal surgical necrotizing enterocolitis Misty Good1* , Tianjiao Chu2,5, Patricia Shaw5, Lora McClain4, Austin Chamberlain5,6, Carlos Castro5, Jamie M. Rimer1, Belgacem Mihi1, Qingqing Gong1, Lila S. Nolan1, Krista Cooksey1, Laura Linneman1, Pranjal Agrawal1, David N. Finegold3 and David Peters2,3,4,5*
Abstract Background: Necrotizing enterocolitis (NEC) remains one of the overall leading causes of death in premature infants, and the pathogenesis is unpredictable and not well characterized. The aim of our study was to determine the molecular phenotype of NEC via transcriptomic and epithelial cell-specific epigenomic analysis, with a specific focus on DNA methylation. Methods: Using laser capture microdissection, epithelial cell-specific methylation signatures were characterized by whole-genome bisulfite sequencing of ileal and colonic samples at the time of surgery for NEC and after NEC had healed at reanastomosis (n = 40). RNA sequencing was also performed to determine the transcriptomic profile of these samples, and a comparison was made to the methylome data. Results: We found that surgical NEC has a considerable impact on the epigenome by broadly increasing DNA methylation levels, although these effects are less pronounced in genomic regions associated with the regulation of gene expression. Furthermore, NEC-related DNA methylation signatures were influenced by tissue of origin, with significant differences being noted between colon and ileum. We also identified numerous transcriptional changes in NEC and clear associations between gene expression and DNA methylation. Conclusions: We have defined the intestinal epigenomic and transcriptomic signatures during surgical NEC, which will advance our understanding of disease pathogenesis and may enable the development of novel precision medicine approaches for NEC prediction, diagnosis and phenotyping. Keywords: DNA methylation, Epigenetics, Necrotizing enterocolitis, Intestinal epithelium, Neonatal Introduction Necrotizing enterocolitis remains a leading cause of death in premature infants [1–3] for which there remain limited treatment options, no reliable biomarkers and the *Correspondence: [email protected]; [email protected] 1 Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine/St. Louis Children’s Hospital, 660 S. Euclid Ave. Campus, Box 8208, St. Louis, MO 63110, USA 2 Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA 15213, USA Full list of author information is available at the end of the article
pathogenesis remains unpredictable. NEC can rapidly take its toll on a growing premature infant to an urgent need of cardiorespiratory support leading to intestinal resection for necrotic bowel a few hours later. The precise disease mechanisms leading to surgical NEC (sNEC) remain ill defined, likely in part because few intestinal samples ar
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