MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation

DNA methylation silences gene expression. In neurones, methylated DNA is recognised by a protein called MeCP2 to silence these genes and maintain function of nerve cells. Mutations to MeCP2 cause Rett syndrome, a severe neurological disorder. In mouse neurones, MeCP2 co-localises with large condensates at silenced heterochromatin at the pericentromere. From this data many scientists hypothesised that MeCP2 forms condensates on heterochromatin via liquid-liquid phase separation. In this study Pantier and colleagues present data which challenges this hypothesis.

Pantier and colleagues first demonstrate that MeCP2 is recruited to chromatin by interacting specifically with methylated DNA, rather than indiscriminately to heterochromatin. They also show that MeCP2 condensates do not behave in a fashion which is consistent with liquid-liquid phase separation, as the size of MeCP2 condensates remains constant as the concentration is increased in live cells. Finally, through imaging MeCP2 in the cells of 16 different species, the researchers demonstrate that the MeCP2 condensates seen in mouse cells are absent in most species, including humans, where MeCP2 is found to be more diffuse throughout the nucleus. The researchers note that organisms in which MeCP2 condensates are present have methylation rich satellite DNA, and showed that cells from a mouse sub-species naturally lacking these elements (Mus spretus) have a diffuse MeCP2 distribution. These data show that MeCP2 condensation at the pericentromere is a species specific phenomenon caused by the presence of repetitive methylated DNA satellites in these species, rather than MeCP2 phase separation.