By hook or by crook: multifaceted DNA-binding properties of MeCP2

Abstract

Two new studies reveal novel DNA-binding properties of MeCP2, mutations of which cause Rett syndrome. Baker et al. report critical roles for the AT-hook domain of MeCP2 in chromatin organization and clinical features of Rett syndrome. Mellén et al. find the methyl-CpG-binding domain of MeCP2 interacts with hydroxymethyl-CpG.

Figure 1. MeCP2 Exhibits Multifaceted DNA-Binding Properties to Regulate Different Chromatin States

(A) A schematic diagram of MeCP2 structure and summary of findings from three different MeCP2 mutations investigated in Baker et al. and Mellén et al. The methyl-CpG-binding domain (MBD) of MeCP2 is involved in the interaction with 5mC, 5hmC and ATRX, whereas the AT-hook domain within the transcription repressor domain (TRD) interacts with AT-rich DNA. MeCP2-R133C loses binding affinity to 5hmC, but retains 5mC-binding affinity. MeCP2-R133C binds very weakly to ATRX, and mutant cells almost completely lose ATRX pericentric heterochromatin (PCH) localization (Nan et al., 2007). Both MeCP2-R270X and MeCP2-G273X retain in vitro ATRX-binding affinity, but ATRX gradually loses its localization to PCH earlier in MeCP2-R270X mutant neurons and later in MeCP2-G273X mutants. The MeCP2 R133C phenotype is from human patients, and the mouse model remains to be examined. (B) A schematic representation of MeCP2 in heterochromatin (compact chromatin) and euchromatin (open chromatin) in the neuronal nucleus. In neurons, higher amounts of MeCP2 exist in euchromatin than in heterochromatin. Histone H1, which induces highly organized and compact chromatin structure, competes with MeCP2 in binding to linker DNA. In heterochromatin, chromatin is highly organized, DNA is highly methylated, and 5mC-bound MeCP2 mostly interacts with repressive chromatin remodelers and transcription repressors. In euchromatin, chromatin is less compact, DNA is more hydroxymethylated or unmethylated, and 5hmC-bound MeCP2 mostly interacts with transcription activators. ATRX interacts with MeCP2 and loses its localization when MeCP2 bears a mutation disrupting the AT-hook domain in the TRD.