NEC-Associated DNA Methylation Signatures in Colon are Evident in Stool Samples of Affected Individuals

Abstract

Neonatal necrotizing enterocolitis (NEC) is a devastating and unpredictable gastrointestinal disease with a high mortality rate in premature infants. Currently, no predictive or diagnostic biomarkers exist for NEC. Clinical intervention is reactive to the overt manifestations of disease resulting in high levels of morbidity and mortality. To better understand the molecular mechanisms that underpin NEC, we have undertaken a high resolution genome wide epigenomic analysis using solution phase hybridization and next generation DNA sequencing of bisulfite converted DNA. Our data reveal a broad and significant genomic hypermethylation in surgical NEC tissues compared to non-NEC controls. These changes were found to be far more pronounced in regions outside CpG islands and gene regulatory elements, which suggests that NEC-specific hypermethylation is not a non-specific global phenomenon. We identified a number of important biological pathways that are dysregulated in NEC and observed a clear association between NEC methylation changes and gene expression. Significantly, we found that the same patterns of global methylation identified in surgical NEC tissue are also detectable in stool samples from affected infants. To our knowledge, this is the first evidence of a methylomic signature that is both associated with NEC and detectable non-invasively. These findings point towards a new opportunity for the development of novel screening, diagnostic and phenotyping methods for NEC that could be deployed in the NICU for improved detection of this devastating disease.