Regulation of the expression of tumor necrosis factor-related genes by abnormal histone H3K27 acetylation: Implications for neural tube defects

The association between apoptosis and neural tube defects (NTDs) is recognized as important, however, the precise link remains to be elucidated. Epigenetic modifications in human NTDs have been detected previously. In the present study, the occurrence of epigenetic modifications in apoptosis-related genes was investigated in a retinoic acid (RA)-induced mouse NTD model. Among 84 key genes involved in programmed cell death, 13 genes, including tumor necrosis factor (Tnf), annexin A5, apoptosis inhibitor 5, Bcl2-associated athanogene 3, baculoviral IAP repeat-containing 3, caspase (Casp)12, Casp4, Casp8, lymphotoxin β receptor, NLR family, apoptosis inhibitory protein 2, TNF receptor superfamily (Tnfrsf)1a, TNF superfamily (Tnfs)f10 and Tnfsf12, were downregulated, whereas nucleolar protein 3 was upregulated in the RA-induced NTD mice. Chromatin immunoprecipitation assays revealed that the regulatory regions of these differentially expressed TNF-related genes showed reduced histone H3K27 acetylation in NTDs, compared with control mice without NTDs. Reverse transcription-quantitative polymerase chain reaction revealed that H3K27ac-binding to the differentially regulated genes was markedly decreased in the NTD mice, whereas binding to the unchanged genes Casp3 and Nfkb1 was unaffected. In conclusion, certain TNF-related genes appeared to be downregulated in NTDs, possibly as a result of abnormal histone H3K27 acetylation. These results shed new light on the epigenetic dysregulation of apoptosis-related genes in NTDs.