Folate deficiency reduced aberrant level of DOT1L-mediated histone H3K79 methylation causes disruptive SHH gene expression involved in neural tube defects

Abstract

Abstract Background Neural tube defects (NTDs) are one of the most severe congenital abnormalities characterized by failures of the neural tube to close during early embryogenesis. Maternal folate deficiency could impact the occurrence of NTDs, however, the mechanisms involved in the cause of NTDs are poorly defined. Results Here, we report that histone H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) expression was significantly downregulated, and low levels of H3K79me2 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Using ChIP-seq assays, we found that a decrease of H3K79me2 downregulates the expression of Shh and Sufu in mouse embryonic stem cells (mESC) under folate deficiency. Interestingly, folate antagonist methotrexate treatment led to attenuation of H3K79me2 due to Dot1l, affecting Shh and Sufu genes regulation. Upon further analysis, we find that the genes Shh and Sufu are both downregulated in the brain tissues of mice and humans with NTDs. There was a positive correlation between the transcription levels of Shh, Sufu and the protein levels of DOT1L by Pearson correlation analysis. Conclusion Our results indicate that abnormal Shh and Sufu genes expression reduced by aberrant Dot1l-mediated H3K79me2 levels could be the cause of NTDs occurrence.

Keywords

• Histone methylation
• Neural tube defects (NTDs)
• Methotrexate (MTX)
• Disruptor of telomeric silencing 1-like (DOT1L)
• Sonic hedgehog (SHH)-related genes