MeCP2 requires interactions with nucleosome linker DNA to read chromatin DNA methylation

Watson, J.A., Alexander-Howden. B.K., Hall, T.S., Wear, M.A., McGhie, F., Clifford, G., Wapenaar, H., Zou, J., Bird, A., and Wilson, M.D.

By Noor Fatima Khalid, Davies Lab.

Rett syndrome is a genetic neurological disorder affecting young females. Although rare, this genetic disorder causes developmental delays or regression leading to loss of acquired speech and motor skills often leading to breathing abnormalities and even seizures. Rett syndrome is caused by mutations in the gene encoding MeCP2 (Methyl-CpG-binding protein 2) protein. MeCP2 recognises methylated DNA directly via its methyl-CpG-binding domain (MBD). However, DNA is packed and inaccessible inside of a complex called nucleosomes and it is unclear as to whether and how MeCP2 accesses these methylated sites.

To answer this scientific question, the Wilson lab designed nucleosomes with methylated cytosines at specific positions on the DNA and investigated how different regions of MeCP2 interacts with them. They found that the MBD recognised methylated sites in the linker DNA (DNA stretch between two nucleosomes) but could not bind to methylation sites within the core of the nucleosome. On the other hand, full-length MeCP2 recognised methylated sites at multiple positions within the nucleosome even including the sites in contact with the core of the nucleosome.

They extended this to show that the linker DNA stretching between the nucleosomes was essential for DNA methylation binding. Longer linker lengths led to improved binding, while removing the linker DNA greatly reduced MeCP2 binding. Further experiments revealed that a central region of MeCP2 outside MBD interacts with the linker DNA and also contributes to recognizing methylated nucleosomal DNA ultimately affecting binding dynamics inside of cells. They also observed histone H1 (H1 is linker histone rather than a core histone forming nucleosomes) interferes with MeCP2 binding by competing for linker DNA, suggesting a balance is stuck between these two abundant proteins.

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