Neuronal non-CG methylation is an essential target for MeCP2 function
DNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the bi...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2021
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| _version_ | 1826274599501824000 |
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| author | Tillotson, R Cholewa-Waclaw, J Chhatbar, K Connelly, JC Kirschner, SA Webb, S Koerner, MV Selfridge, J Kelly, DA De Sousa, D Brown, K Lyst, MJ Kriaucionis, S Bird, A |
| author_facet | Tillotson, R Cholewa-Waclaw, J Chhatbar, K Connelly, JC Kirschner, SA Webb, S Koerner, MV Selfridge, J Kelly, DA De Sousa, D Brown, K Lyst, MJ Kriaucionis, S Bird, A |
| author_sort | Tillotson, R |
| collection | OXFORD |
| description | DNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the biological significance of the dual-binding specificity of MeCP2, we replaced its DNA binding domain with an orthologous domain from MBD2, which can only bind mCG motifs. Knockin mice expressing the domain-swap protein displayed severe Rett-syndrome-like phenotypes, indicating that normal brain function requires the interaction of MeCP2 with sites of non-CG methylation, specifically mCAC. The results support the notion that the delayed onset of Rett syndrome is due to the simultaneous post-natal accumulation of mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2 null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of relevance to the Rett syndrome phenotype. |
| first_indexed | 2024-03-06T22:45:54Z |
| format | Journal article |
| id | oxford-uuid:5d2a4007-38ea-474b-a829-fdb996990e40 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:45:54Z |
| publishDate | 2021 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:5d2a4007-38ea-474b-a829-fdb996990e402022-03-26T17:32:40ZNeuronal non-CG methylation is an essential target for MeCP2 functionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5d2a4007-38ea-474b-a829-fdb996990e40EnglishSymplectic ElementsCell Press2021Tillotson, RCholewa-Waclaw, JChhatbar, KConnelly, JCKirschner, SAWebb, SKoerner, MVSelfridge, JKelly, DADe Sousa, DBrown, KLyst, MJKriaucionis, SBird, ADNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the biological significance of the dual-binding specificity of MeCP2, we replaced its DNA binding domain with an orthologous domain from MBD2, which can only bind mCG motifs. Knockin mice expressing the domain-swap protein displayed severe Rett-syndrome-like phenotypes, indicating that normal brain function requires the interaction of MeCP2 with sites of non-CG methylation, specifically mCAC. The results support the notion that the delayed onset of Rett syndrome is due to the simultaneous post-natal accumulation of mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2 null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of relevance to the Rett syndrome phenotype. |
| spellingShingle | Tillotson, R Cholewa-Waclaw, J Chhatbar, K Connelly, JC Kirschner, SA Webb, S Koerner, MV Selfridge, J Kelly, DA De Sousa, D Brown, K Lyst, MJ Kriaucionis, S Bird, A Neuronal non-CG methylation is an essential target for MeCP2 function |
| title | Neuronal non-CG methylation is an essential target for MeCP2 function |
| title_full | Neuronal non-CG methylation is an essential target for MeCP2 function |
| title_fullStr | Neuronal non-CG methylation is an essential target for MeCP2 function |
| title_full_unstemmed | Neuronal non-CG methylation is an essential target for MeCP2 function |
| title_short | Neuronal non-CG methylation is an essential target for MeCP2 function |
| title_sort | neuronal non cg methylation is an essential target for mecp2 function |
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