Repeat after Me(CP2)!

Abstract

A motif of dinucleotide repeats in the genome may be associated with Rett syndrome Rett syndrome (RTT) is a devastating neurodevelopmental disease caused primarily by loss-of-function mutations in methyl-CpG-binding protein 2 (MECP2) (1). MeCP2 is a DNA binding protein (2) that controls gene expression, but the precise molecular mechanism by which MeCP2 loss drives RTT pathology remains unclear, partially because a distinct DNA motif that specifies MeCP2-DNA interactions is lacking. On page 1411 of this issue, Ibrahim et al. (3) demonstrate that MeCP2 binds modified cytosine in cytosine-adenine (CA) dinucleotide repeats, providing a new signature DNA motif for MeCP2 binding. MeCP2 protects CA repeats from high nucleosome occupancy, raising questions about the consequence of this binding on maintaining chromatin structure in neurons.