Wellcome Centre for Cell Biology, University of Edinburgh, The Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK.
Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Mol Cell. 2021 Mar 18;81(6):1260-1275.e12. doi: 10.1016/j.molcel.2021.01.011. Epub 2021 Feb 8.
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.
DNA 甲基化通过蛋白质 MeCP2 参与神经元生物学，其突变导致雷特综合征。MeCP2 将 NCOR1/2 共抑制复合物募集到 CG 二核苷酸中的甲基化胞嘧啶，但也募集到富含神经元中的非 CG 甲基化位点。为了测试 MeCP2 的双重结合特异性的生物学意义，我们用来自 MBD2 的同源结构域替换了其 DNA 结合结构域，MBD2 只能结合 mCG 基序。表达结构域交换蛋白的基因敲入小鼠表现出严重的雷特综合征样表型，表明正常的大脑功能需要 MeCP2 与非 CG 甲基化位点，特别是 mCAC 的相互作用。研究结果支持这样一种观点，即雷特综合征的延迟发作是由于 mCAC 及其阅读器 MeCP2 的同时在出生后的积累所致。有趣的是，在 Mecp2 缺失和结构域交换小鼠中失调的基因都与其他神经障碍有关，这可能突出了与雷特综合征表型相关的潜在靶点。
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