A brain-derived MeCP2 complex supports a role for MeCP2 in RNA processing

Methyl CpG binding protein 2 (MeCP2) was originally characterized as a transcriptional repressor that preferentially bound methylated DNA, however, recent data indicates MeCP2 is a multifunctional protein. MeCP2 is now shown to associate with expressed genes as well as repressed genes indicating its gene regulatory function is context dependent. In addition, MeCP2 is involved in nuclear organization and proposed to regulate mRNA splicing. Mutations in MECP2 are linked to the severe postnatal neurodevelopmental disorder Rett Syndrome (RTT). To further understand MeCP2 and potential roles in RTT pathogenesis, we have employed a biochemical approach to identify the MeCP2 protein complexes present in the mammalian brain. Here we show that MeCP2 exists in at least four biochemically distinct pools in the brain. We characterize one novel brain-derived MeCP2 complex that contains the splicing factor Prpf3 and Sdccag1. MeCP2 directly interacts with both Prpf3 and Sdccag1 in vitro independent of nucleic acids and certain RTT truncation disrupt the MeCP2-Prpf3-Sdccag1 complex. In addition, MeCP2 is localized to transcriptionally active Xenopus lampbrush chromosome loops and, both MeCP2 and Prpf3 associate in vivo with mRNAs of some genes thought to be regulated by MeCP2. This data supports a regulatory role for MeCP2 in mRNA biogenesis and suggests an additional mechanism for RTT pathophysiology