Folate deficiency induced H2A ubiquitination to lead to downregulated expression of genes involved in neural tube defects

Autor: Jianxin Wu, Shan Wang, Juan Yu, Xue Li, Xiyue cheng, Ting Zhang, Pei Pei, Jinying Shen
Rok vydání: 2019
Předmět:
lcsh:QH426-470
PAX6 Transcription Factor
Down-Regulation
Embryonic Development
Ataxia Telangiectasia Mutated Proteins
Biology
Histones
Mice
03 medical and health sciences
Folic Acid
0302 clinical medicine
Downregulation and upregulation
Genetics
medicine
Animals
CDX2 Transcription Factor
Neural Tube Defects
RNA
Small Interfering
Histone H2A monoubiquitination
Molecular Biology
Embryonic Stem Cells
030304 developmental biology
0303 health sciences
Neural tube defect
Histone ubiquitination
Research
Neural tube closure-related genes
Embryogenesis
Ubiquitination
Neural tube
Proto-Oncogene Proteins c-mdm2
medicine.disease
Cell biology
Mice
Inbred C57BL
Folate antagonist methotrexate
lcsh:Genetics
Methotrexate
medicine.anatomical_structure
Mouse double minute 2 homolog (Mdm2
MDM2)
biology.protein
Mdm2
RNA Interference
PAX6
030217 neurology & neurosurgery
DNA Damage
Protein Binding
Zdroj: Epigenetics & Chromatin
Epigenetics & Chromatin, Vol 12, Iss 1, Pp 1-19 (2019)
ISSN: 1756-8935
DOI: 10.1186/s13072-019-0312-7
Popis: Background Neural tube defects (NTDs) are common congenital malformations resulting in failure of the neural tube closure during early embryonic development. Although it is known that maternal folate deficiency increases the risk of NTDs, the mechanism remains elusive. Results Herein, we report that histone H2A monoubiquitination (H2AK119ub1) plays a role in neural tube closure. We found that the folate antagonist methotrexate induced H2AK119ub1 in mouse embryonic stem cells. We demonstrated that an increase in H2AK119ub1 downregulated expression of the neural tube closure-related genes Cdx2, Nes, Pax6, and Gata4 in mouse embryonic stem cells under folate deficiency conditions. We also determined that the E3 ligase Mdm2 was responsible for the methotrexate-induced increase in H2AK119ub1 and downregulation of neural tube closure-related genes. Surprisingly, we found that Mdm2 is required for MTX-induced H2A ubiquitination and is recruited to the sites of DSB, which is dependent on DNA damage signaling kinase ATM. Furthermore, folic acid supplementation restored H2AK119ub1 binding to neural tube closure-related genes. Downregulation of these genes was also observed in both brain tissue of mouse and human NTD cases, and high levels of H2AK119ub1 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Pearson correlation analysis showed a significant negative correlation between expression of the neural precursor genes and H2AK119ub1. Conclusion Our results indicate that folate deficiency contributes to the onset of NTDs by altering H2AK119ub1 and subsequently affecting expression of neural tube closure-related genes. This may be a potential risk factor for NTDs in response to folate deficiency.
Databáze: OpenAIRE
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