Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin

Abstract

Summary Methylated CpG Binding Protein 2 (MeCP2) is a nuclear protein named for its ability to selectively recognize methylated DNA. Much attention has been focused on understanding MeCP2 structure and function in the context of its role in Rett syndrome, a severe neurodevelopmental disorder that afflicts one in 10,000–15,000 girls. Early studies suggested a connection between DNA methylation, MeCP2, and establishment of a repressive chromatin structure at specific gene promoters. However, it is now recognized that MeCP2 can both activate and repress specific genes depending on the context. Likewise, in the cell, MeCP2 is bound to unmethylated DNA and chromatin in addition to methylated DNA. Thus, to understand the molecular basis of MeCP2 functionality, it is necessary to unravel the complex interrelationships between MeCP2 binding to unmethylated and methylated regions of the genome. MeCP2 is unusual and interesting in that it is an intrinsically disordered protein, that is, much of its primary sequence fails to fold into secondary structure and yet is functional. The unique structure of MeCP2 is the subject of the first section of this article. We then discuss recent investigations of the in vitro binding of MeCP2 to unmethylated and methylated DNA, and the potential ramifications of this work for in vivo function. We close by focusing on mechanistic studies indicating that the binding of MeCP2 to chromatin results in compaction into local (secondary) and global (tertiary) higher order structures. MeCP2 also competes with histone H1 for nucleosomal binding sites. The recent finding that MeCP2 is found at near stoichiometric levels with nucleosomes in neuronal cells underscores the multiple modes of engagement of MeCP2 with the genome, which include the cooperative tracking of methylation density.

Rett Syndrome and MeCP2

“…Even though MeCP2 is mostly known as a methyl binding protein, several studies have shown its binding to unmethylated DNA as well (Baubec et al 2013;Hansen et al 2010). In the absence of DNA methylation, MeCP2 is localized to genomic regions with open/ accessible chromatin structure, independent of MeCP2 protein interacting partners (Baubec et al 2013).…”

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

“…Among the regulatory sites bound by HMGN1 is the promoter of the gene coding for methyl CpG-binding protein 2 (MeCP2), a nuclear protein that is expressed postnatally during mammalian brain development and is highly abundant in neurons (23). Despite its name, MeCP2 can bind both methylated and unmethylated CpG sequences (24,25) and can either repress (26 -28) or activate (29,30) transcription. Mutations or altered levels of MeCP2 can lead to neurodevelopmental disorders such as Rett syndrome, mental retardation, learning disabilities, autism spectrum disorders (ASDs) (31,32) repetitive behavior, hypotonia, and anxiety (33).…”

DNA Binding Restricts the Intrinsic Conformational Flexibility of Methyl CpG Binding Protein 2 (MeCP2)

“…4 -6, reviewed in Ref. 7), chromatin (4,(7)(8)(9), and RNA (10), MeCP2 interacts with many different nuclear proteins, including Sin3a (11), SUV39H1 (12), HP1 (13), DNMT1 (14), Ski and N-COR (15), PU.1 (16), BRM (17), and ATRX (18). Although originally hypothesized to be a specific repressor of methylated genes (11), MeCP2 is now recognized to be multifunctional, with roles in transcriptional activation and repression (19), RNA processing (20), and chromatin organization (8,3,21) (reviewed in Ref.…”