Single-cell multiome profiling reveals neuronal bias of modulatory role of MeCP2 phosphorylation

Several MeCP2 phosphorylation sites have been identified and studied individually. However, the combinatorial effect of phosphorylation at multiple sites has not been directly examined.

Building on previous studies characterizing single mutations of MeCP2 phosphorylation sites, we created a mouse model carrying two mutations, serine 80 to alanine and serine 421 to glutamic acid (S80A;S421E, or A;E), in which the MeCP2 protein phosphorylation is fixed in a state observed in active neurons. A battery of behavioral tests was conducted to characterize the functional outcomes at the whole animal level, followed by two independent single-cell/nuclei level multiome profiling assays to characterize altered molecular pathways, and regulatory pattern biased towards glutamatergic neurons on both transcription and chromatin level.