Neuronal non-CG methylation is an essential target for MeCP2 function.

Autor:	Tillotson R; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Cholewa-Waclaw J; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Chhatbar K; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Connelly JC; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Kirschner SA; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK., Webb S; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Koerner MV; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Selfridge J; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Kelly DA; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., De Sousa D; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Brown K; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Lyst MJ; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK., Kriaucionis S; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK., Bird A; Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK. Electronic address: a.bird@ed.ac.uk.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Mar 18; Vol. 81 (6), pp. 1260-1275.e12. Date of Electronic Publication: 2021 Feb 08.
DOI:	10.1016/j.molcel.2021.01.011
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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