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Immunostaining for DNA Modifications: Computational Analysis of Confocal Images
Published on: September 7, 2017
Dnmt3a-mediated abnormal DNA methylation is associated with myelination deficits in offspring of advanced maternal
Chunxue Jiang1, Xinru Yan1, Man Xu1
1Department of Neurology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
Background:
Advanced maternal age (AMA) threatens offspring brain development, yet its neurodevelopment-disrupting mechanisms remain poorly understood. Our prior work has suggested that AMA may impair myelin development in offspring, accompanied by increased Dnmt3a expression and DNA methylation levels in the hippocampus. This study explores whether Dnmt3a mediates myelination defects in offspring of AMA rats.
Methods:
Lentiviral vectors were intracerebroventricularly administered to modulate Dnmt3a expression in AMA offspring after birth. Protein expression was analyzed by western blotting and immunofluorescence at postnatal days (P) 7, 14, and 28. Myelin development was evaluated at P28 using transmission electron microscopy, immunofluorescence, luxol fast blue staining, and glycine silver staining. Cognitive function was assessed using the novel object recognition test from P23 to P24.
Results:
AMA offspring exhibited impaired oligodendrocyte precursor cell (OPC) maturation and abnormal myelination during early postnatal brain development. Inhibition of Dnmt3a increased the expression of CNPase, MBP, and Olig2, which are associated with oligodendrocyte lineage maturation and myelination, and alleviated myelin deficits and cognitive impairment. Furthermore, Dnmt3a inhibition reduced 5-methylcytosine levels in PDGFR-α-positive cells and decreased Dnmt3a expression in Olig2-positive cells. In contrast, Dnmt3a overexpression did not significantly alter myelination-related phenotypes.
Conclusion:
In conclusion, Dnmt3a dysregulation could be associated with altered OPC maturation and myelination in AMA offspring, possibly mediated by epigenetic mechanisms involving Olig2. Dnmt3a downregulation partially restores oligodendrocyte lineage maturation, myelin development, and cognitive function. These findings suggest that Dnmt3a may serve as a potential molecular target for further investigation in the prevention of neurodevelopmental impairments associated with AMA.
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