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Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects.
- Source :
-
Nature communications [Nat Commun] 2018 Aug 24; Vol. 9 (1), pp. 3436. Date of Electronic Publication: 2018 Aug 24. - Publication Year :
- 2018
-
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.
- Subjects :
- Adult
Animals
Brain drug effects
Brain metabolism
Chick Embryo
DNA (Cytosine-5-)-Methyltransferases metabolism
DNA Helicases metabolism
Female
HEK293 Cells
Homocysteine analogs & derivatives
Humans
Male
Nuclear Proteins metabolism
Transcription Factors metabolism
Young Adult
DNA Methyltransferase 3B
Histones metabolism
Homocysteine metabolism
Neural Tube Defects metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30143612
- Full Text :
- https://doi.org/10.1038/s41467-018-05451-7