Abstract
Neural tube defects (NTDs) are serious congenital malformations. Excessive maternal homocysteine (Hcy) increases the risk of NTDs, while its mechanism remains elusive. Here we report the role of histone homocysteinylation in neural tube closure (NTC). A total of 39 histone homocysteinylation sites are identified in samples from human embryonic brain tissue using mass spectrometry. Elevated levels of histone KHcy and H3K79Hcy are detected at increased cellular Hcy levels in human fetal brains. Using ChIP-seq and RNA-seq assays, we demonstrate that an increase in H3K79Hcy level down-regulates the expression of selected NTC-related genes including Cecr2, Smarca4, and Dnmt3b. In human NTDs brain tissues, decrease in expression of CECR2, SMARCA4, and DNMT3B is also detected along with high levels of Hcy and H3K79Hcy. Our results suggest that higher levels of Hcy contribute to the onset of NTDs through up-regulation of histone H3K79Hcy, leading to abnormal expressions of selected NTC-related genes.
Highlights
Neural tube defects (NTDs) are serious congenital malformations
Our results suggest that high Hcy levels may increase the expression level of histone H3K79Hcy, resulting in a decrease in expression of some neural tube closure (NTC)-related genes, which lead to NTDs formation
Most all of the identified histone KHcy sites are the sites that have been shown to be subject to other types of modifications[17], including H3K27, H3K36, and H3K79 whose modification is important for chromatin structure and function[18]
Summary
Neural tube defects (NTDs) are serious congenital malformations. Excessive maternal homocysteine (Hcy) increases the risk of NTDs, while its mechanism remains elusive. In human NTDs brain tissues, decrease in expression of CECR2, SMARCA4, and DNMT3B is detected along with high levels of Hcy and H3K79Hcy. Our results suggest that higher levels of Hcy contribute to the onset of NTDs through up-regulation of histone H3K79Hcy, leading to abnormal expressions of selected NTC-related genes. An array of histone modifications including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation have been shown to be associated with changes in chromatin organization, gene activation, silencing, and several other nuclear functions[15,16] These findings suggest that Hcy could act as a substrate to modify histones and aberrant histone homocysteinylation may be involved in the failure of NTC. Our results suggest that high Hcy levels may increase the expression level of histone H3K79Hcy, resulting in a decrease in expression of some NTC-related genes, which lead to NTDs formation
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