| First Author | Tillotson R | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 6 | Pages | 1260-1275.e12 |
| PubMed ID | 33561390 | Mgi Jnum | J:309631 |
| Mgi Id | MGI:6707955 | Doi | 10.1016/j.molcel.2021.01.011 |
| Citation | Tillotson R, et al. (2021) Neuronal non-CG methylation is an essential target for MeCP2 function. Mol Cell 81(6):1260-1275.e12 |
| abstractText | 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. |
