Rett syndrome and MeCP2

Abstract

Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

Fig. 1

The structure of the MECP2/Mecp2 gene and MeCP2 protein. a The MECP2/Mecp2 gene is located in X-chromosome (Xq28), flanked by the RCP and IRAK genes. b The schematic of the MECP2/Mecp2 gene is shown that is composed of four exons (exon 1–4) and three introns (intron 1–3). The gene has three polyadenylation sites at the 3′UTR. The sizes of each exonic and intronic region in human MECP2 and mouse Mecp2 genes are indicated. c The generation of two MeCP2 isoforms: MeCP2E1 and MeCP2E2. The translation start site (ATG) for each isoform is indicated by arrows. MeCP2E1 isoform is encoded by exons 1, 3 and 4. MeCP2E2 isoform is encoded by exons 2, 3 and 4. Red coding sequence. Green noncoding sequence. d Protein structure of human MeCP2E1 and MeCP2E2. The human MeCP2E1 and MeCP2E2 are 498 and 486 amino acids in size, respectively. In contrast, the mouse MeCP2E1 and MeCP2E2 are 501 and 484 amino acids in size, respectively. MBD methyl-CpG-binding domain, ID inter-domain, TRD transcriptional repression domain, CTD C-terminal domain, NTD N-terminal domain, AT-hook a domain found within the TRD which allows binding to adenine–thymine (AT) rich DNA

Fig. 2

Distribution of known MeCP2 mutations and the interactions/functions abolished due to mutations. The well-known mutations found in Rett Syndrome patients and the loss of interactions and functions of MeCP2 due these mutations are illustrated. MBD methyl-CpG-binding domain, ID inter-domain, TRD transcriptional repression domain, CTD C-terminal domain, NTD N-terminal domain, AT AT-hook domain, 5mC 5-methylcytosine, 5hmC 5-hy-droxymethylcytosine. The amino acid numbers are according to the location on MeCP2E2 isoform

Fig. 3

Summary of DNA methylation-mediated regulation of Mecp2 isoforms in response to Decitabine exposure during neural stem cell differentiation. DNA methylation at three regulatory elements found within the Mecp2 promoter (R1–R3) and Mecp2 intron 1 (R4–R6) was analyzed by bisulfite pyrosequencing, in untreated control and Decitabine-treated neural stem cells. DNA Methylation at specific Mecp2 regulatory elements (R2 in the Mecp2 promoter and R4–R6 in the intron 1) were reduced (DNA demethylation), in response to Decitabine exposure. These changes in DNA methylation are correlated with upregulation (↑) of Mecp2/MeCP2 (total), Mecp2e1/MeCP2E1 and unchanged levels (↕) of Mecp2e2. The effects of Decitabine on MeCP2E2 protein levels are unknown (?). The information was extracted from (Liyanage et al. 2013). R region, C cytosine, 5mC 5-methylcytosine

Fig. 4

Known regulatory mechanisms of MECP2/Mecp2 gene. The MECP2/Mecp2 gene is regulated transcriptionally and posttranscriptionally by multiple mechanisms. (1) The MECP2 promoter contains positive and negative regulatory elements (+RE and −RE) which are known to regulate MECP2 expression. Both MECP2/Mecp2 genes harbor CpG islands and several CpG dinucleotides regulated by DNA methylation. (2) Cis-regulatory elements are found in intragenic regions of MECP2 gene as well as intragenic regions. There are two silencer elements (S1–S2) and four enhancer elements (E1–E4). P promoter. (3) MECP2/Mecp2 3′UTR contains polyadenylation sites and Cis-acting elements (yellow boxes) which harbor binding sites for trans-acting factors involved in polyadenylation. There transcript variants are generated by polyadenylation (1.8, 7.5 and 10.2 kb). (4) Binding of miRNAs to miRNA response elements (MRE) at the 3′UTR involves in posttranscriptional regulation of MECP2/Mecp2. (5) Changes in histone modifications in response to binding of regulatory proteins regulate Mecp2/MECP2 expression. For example, binging of HMGN1 induces modifications in histones and thereby changes the chromatin structure. There is a differential enrichment of histone posttranslational modifications (PTMs) across the MECP2/Mecp2 gene. As an example, the distribution of active histone marks H3K9Ac and H3K27Ac across the MECP2 gene in three cell types (HeLa, HepG2 and HUVEC) is shown (data extracted from http://genome.ucsc.edu/; February 2009 assembly)