DNA Methylome Mapping Identifies Epigenetic Abnormalities in Intestinal Lymphocyte Regulation in Human Necrotizing Enterocolitis

Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis

“…In addition to HDAC8, we identified several other histone deacetylases with abnormal expression in NEC. Based on our previous findings that epigenetic reprogramming factors, including genes encoding histone H3K27 demethylation-associated proteins, enhancer binding proteins, and histone deacetylases, are methylated in NEC, 29 we believe that the regulation of histone modification plays a very important role in the occurrence and development of NEC. Previous studies have suggested that SCFAs alter chemokine expression in the epithelium and enhance the recruitment of neutrophils and lymphocytes into the intestine.…”

“… 14 The most well-known epigenetic changes are DNA methylation and post-translational modifications on histones. 15 Emerging evidence indicates that DNA methylation contributes to changes in gene transcription and the establishment of signaling networks in NEC, 16 , 17 , 18 but knowledge about histone modifications that occur in NEC is limited. Histone deacetylases (HDACs) are a family of enzymes that alter gene expression by deacetylating histones and are associated with multiple biological events, 19 , 20 and the expression of HDACs is often perturbed in cancer, neurological syndromes, and immune disorders.…”

DNA methylation in necrotizing enterocolitis

“…DNA methylation studies in NEC research are in their early stages (Refs 13, 14, 15, 16, 115, 116), but scientists and clinicians desperately need improved predictive and diagnostic tools for this deadly disease. The clinical implementation and widespread incorporation of cfDNA testing in prenatal care indicate that nucleic acid-based testing can have immense clinical utility.…”

Therapeutic Potential of Gut Microbiota and Its Metabolite Short-Chain Fatty Acids in Neonatal Necrotizing Enterocolitis

“…An association of CpG methylation in the cytokine Oncostatin M (OSM) with NEC has also been observed, which can induce intestinal inflammation [ 47 ]. The hypermethylation of four genes ( MPL , KDM6A , ZNF335 and RASAL3 ) has been reported in the intestine of neonatal NEC, which is associated with lymphocyte proliferation and intestinal epithelial permeability [ 48 ]. Analyses of CpG methylation positions in the intestinal epithelial cells of neonatal NEC revealed a significant hypermethylation in five genes (toll-like receptor 4; TLR4, ENOS , EPO , DEFA5 and VEGFA ) at three sites [ 49 ].…”

“…Gene expression including cytokines and chemokines result from histone and long non-coding RNA (lncRNA) modifications have been linked to immune cell function and inflammation in NEC [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Given that SCFAs have been identified as epigenetic modifier exert anti-inflammatory effects in inflammatory diseases [ 22 , 23 , 42 ], it is likely that SCFA-producing bacteria and SCFAs could perform an epigenetic role in modulating immune responses in the inflamed gut of neonatal NEC by reducing pro-inflammatory cytokines and chemokines.…”