Losing Dnmt3a dependent methylation in inhibitory neurons impairs neural function by a mechanism impacting Rett syndrome
| Autor: | Jacinta Lucero, Joseph R. Ecker, M. Margarita Behrens, Chongyuan Luo, Margaret A. Goodell, Alexander J. Trostle, Kerstin Ure, Joseph R. Nery, Huda Y. Zoghbi, Rosa Castanon, Zhandong Liu, Haijing Jin, Joanna Lopez, Ying-Wooi Wan, Wei Wang, Mark A Durham, Laura A. Lavery |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Mouse Methyl-CpG-Binding Protein 2 Dnmt3a DNA Methyltransferase 3A Mice 0302 clinical medicine Rett syndrome Gene expression inhibitory neuron DNA (Cytosine-5-)-Methyltransferases Biology (General) GABAergic Neurons Regulation of gene expression General Neuroscience Gene Expression Regulation Developmental General Medicine Methylation respiratory system Chromosomes and Gene Expression embryonic structures GABAergic Medicine Female hormones hormone substitutes and hormone antagonists Research Article congenital hereditary and neonatal diseases and abnormalities QH301-705.5 Science Biology General Biochemistry Genetics and Molecular Biology MECP2 03 medical and health sciences medicine Animals Genetic Predisposition to Disease Epigenetics Gene MeCP2 General Immunology and Microbiology medicine.disease nervous system diseases 030104 developmental biology Neuroscience 030217 neurology & neurosurgery non-CpG methylation |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| ISSN: | 2050-084X |
| Popis: | Methylated cytosine is an effector of epigenetic gene regulation. In the brain, Dnmt3a is the sole ‘writer’ of atypical non-CpG methylation (mCH), and MeCP2 is the only known ‘reader’ for mCH. We asked if MeCP2 is the sole reader for Dnmt3a dependent methylation by comparing mice lacking either protein in GABAergic inhibitory neurons. Loss of either protein causes overlapping and distinct features from the behavioral to molecular level. Loss of Dnmt3a causes global loss of mCH and a subset of mCG sites resulting in more widespread transcriptional alterations and severe neurological dysfunction than MeCP2 loss. These data suggest that MeCP2 is responsible for reading only part of the Dnmt3a dependent methylation in the brain. Importantly, the impact of MeCP2 on genes differentially expressed in both models shows a strong dependence on mCH, but not Dnmt3a dependent mCG, consistent with mCH playing a central role in the pathogenesis of Rett Syndrome. |
| Databáze: | OpenAIRE |
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