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

Tillotson, R., Cholewa-Waclaw, J., Chhatbar, K., Connelly, J.C., Kirschner, S.A., Webb, S., Koerner, M.V., Selfridge, J., Kelly, D.A., De Sousa, D., Brown, K., Lyst, M.J., Kriaucionis, S., and Bird, A.

Molecular Cell (2021)

MeCP2 is an epigenetic reader of DNA methylation in two sequence contexts: mCG and mCAC. Tillotson et al. show that mice expressing a chimeric MeCP2 protein that can no longer bind mCAC exhibit severe Rett-syndrome-like phenotypes. The results demonstrate that mCAC binding is an essential property of MeCP2.

Summary of Paper by Lori Koch

Mutations in the gene MECP2 result in a neurological disorder known as Rett Syndrome. MeCP2 protein binds to specific modified DNA sequences mCG (5-methylcytosine guanine) and also mCH, where H=A, C, or T, although it has been shown to prefer mCAC over other forms. In their recent study published in Molecular Cell, scientists in the Bird lab group led by Dr. Rebekah Tillotson determined that loss of MeCP2 binding to mCAC causes Rett Syndrome-like symptoms in mice. To disentangle the importance of MeCP2 binding to mCG versus other mCH nucleotides, the scientists replaced the DNA-binding domain of MeCP2 with a similar part from another protein that only binds to mCG. They confirmed that this mutant protein, which they called MM2, had comparable function, except that it did not recognize mCH DNA. Next, they generated mice where the normal MECP2 gene was replaced with the MM2 mutant allele. These mice displayed motor defects, hind limb clasping, decreased anxiety and premature death, similar to mouse models of Rett syndrome which are deficient in MECP2 function. To further investigate the causes for the disease, the scientists performed RNA sequencing of control, MeCP2-deficient and MM2 mouse neurons. This uncovered a set of 20 disease-associated genes that are dysregulated in both MeCP2-deficient and MM2 neurons, and whose proper expression is likely to depend on MeCP2 binding to mCH specifically. Together, the study emphasizes the power of genetics to dissect gene function in cells and disease.

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