Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects

Nature Communications
Qin ZhangTing Zhang

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.

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Aug 14, 2019·Current Opinion in Pediatrics·Paul Wolujewicz, M Elizabeth Ross
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Datasets Mentioned

BETA
GSE104093
GSE104094

Methods Mentioned

BETA
glycosylation
dot blot
acetylation
ChIP-seq
ChIP
RNA-seq
transfection
affinity purification
dissecting
X-ray

Software Mentioned

PD
DAVID
Xcalibur Qual Browser
QuantStudio
Illumina
nCounter Digital Analyzer
Bioconductor
skyline
RESM
FGNet

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