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Background  Neural tube defects (NTDs) are severe, common birth defects that result from failure of normal neural tube closure during early embryogenesis. Accumulating strong evidence indicates that genetic factors contribute to NTDs etiology, among them,  HOX  genes play a key role in neural tube closure. Although abnormal  HOX  gene expression can lead to NTDs, the underlying pathological mechanisms have not fully been understood.    Method  We detected that H3K27me3 and expression of the  Hox  genes in a retinoic acid (RA) induced mouse NTDs model on E8.5, E9.5 and E10.5 using RNA-sequencing and chromatin immunoprecipitation sequencing assays. Furthermore, we quantified 10  Hox  genes using NanoString nCounter in brain tissue of fetuses with 39 NTDs patients including anencephaly, spina bifida, hydrocephaly and encephalocele.    Results  Here, our results showed differential expression in 26 genes with a > 20-fold change in the level of expression, including 10 upregulated  Hox  genes. RT-qPCR revealed that these 10  Hox  genes were all upregulated in RA-induced mouse NTDs as well as RA-treated embryonic stem cells (ESCs). Using ChIP-seq assays, we demonstrate that a decrease in H3K27me3 level upregulates the expression of  Hox  cluster  A–D  in RA-induced mouse NTDs model on E10.5. Interestingly, RA treatment led to attenuation of H3K27me3 due to cooperate between UTX and Suz12, affecting  Hox  gene regulation. Further analysis, in human anencephaly cases, upregulation of 10  HOX  genes was observed, along with aberrant levels of H3K27me3. Notably,  HOXB4 ,  HOX C4 and  HOX D1 expression was negatively correlated with H3K27me3 levels.    Conclusion  Our results indicate that abnormal  HOX  gene expression induced by aberrant H3K27me3 levels may be a risk factor for NTDs and highlight the need for further analysis of genome-wide epigenetic modification in NTDs.

Reduced H3K27me3 leads to abnormal Hox gene expression in neural tube defects