MeCP2 and Chromatin Compartmentalization

Abstract

Methyl-CpG binding protein 2 (MeCP2) is a multifunctional epigenetic reader playing a role in transcriptional regulation and chromatin structure, which was linked to Rett syndrome in humans. Here, we focus on its isoforms and functional domains, interactions, modifications and mutations found in Rett patients. Finally, we address how these properties regulate and mediate the ability of MeCP2 to orchestrate chromatin compartmentalization and higher order genome architecture.

Keywords: DNA methylation readers; DNA modifications; MeCP2; Rett syndrome; heterochromatin; higher order chromatin structure.

Figure 1

Overview of MeCP2 interaction partners. MeCP2 interaction partners, group by main function and ordered by where they interact within MeCP2, if known. References are given in Table 1. Rectangles indicate proteins with no mapped interaction region within MeCP2. NTD: N-terminal domain; MBD: methyl binding domain; ID: intervening domain; NID: N-CoR interacting domain; CTD: C-terminal domain; TRD: transcriptional repression domain. Amino acid labeling according to mouse MeCP2 isoform e2. Protein domain structure generated using DOG 1.0 software [61].

Figure 2

Diagram showing the high frequency mutation spectrum in Rett syndrome patients. A compendium of RTT mutations can be found in the online RettBASE. Missense mutations are shown above and nonsense mutations below the scheme showing the structure of MeCP2 (MeCP2 domains as in Figure 1). X means point mutation to stop codon, thus generating a truncated protein. Amino acids and substitutions are given according to the single-letter nomenclature. Mutation numbering according to human MeCP2 isoform starting in exon 2.

Figure 3

Role of multivalent interactions in heterochromatin formation. Left: transmission electron microscopy image of a mouse liver cell nucleus at interphase with electron dense regions corresponding to heterochromatin and electron light regions corresponding to euchromatin. NU: nucleoli. Scale bar = 0.5 µm. Middle: graphical representation of heterochromatin. Nucleosomes are tightly packed within heterochromatin and show limited accessibility to multiple factors binding DNA. Right: cartoon showing multivalent interactions that promote heterochromatin formation. Chromatin compaction can be maintained by multivalent interactions involving DNA and multiple proteins. Unmethylated, methylated DNA and posttranslational modifications of histones could recruit multiple protein factors containing intrinsically disordered regions (IDR) (like MeCP2 and HP1). Via these IDR regions multivalent homo and hetero weak interactions take place, promoting the formation of heterochromatin possibly by phase separation.