MECP2

Official Full Name

methyl-CpG binding protein 2

Organism

Homo sapiens

GeneID

4204

Background

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

Synonyms

RS; RTS; RTT; PPMX; MRX16; MRX79; MRXSL; AUTSX3; MRXS13;

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Detailed Information

MeCP2 (Methyl CpG binding protein 2, MeCP2) is the first discovered MBD protein with a length of 53 ka, which has three major functional domains: the MBD binding domain, the N-terminal Transcription repression domain (TRD), and C-terminal domain (CTD). Studies have shown that if the N-terminal MBD domain is deleted, MECP2 can also bind to methylated DNA, but the specificity of binding is significantly reduced, indicating that the interaction of the MBD domain with methylated DNA is essential for the specific binding of MECP2.

MeCP2 acts as an “epigenetic reader” and helps to establish the functional state of chromatin structure. In fact, it interacts with several chromatin remodeling factors, such as HDAC-containing complexes and ATRX. At the molecular level of normal cellular function, MeCP2 is described as a repressor that inhibits gene transcription through chromatin compression.

Figure 1. Schematic to show how MeCP2 regulates target gene expression.（Xu-Rui, et al. 2017）

Relationship Between MeCP2 and Neurological Diseases

Rett syndrome (RTT) is a neurodegenerative disease that is severely affected by the development of psychomotor activity in children. MECP2 is a ReTT pathogenic gene, which is a transcriptional co-receptor A (Sin3A) and Histone deacetylases (HDACs) that bind to methylated CpG islands and complex with Sin3 homologs to regulate gene expression. Moreover, different mutations (point mutations, repeats or deletion mutations) are associated with the severity of the disease and there are approximately 30 types of mutations that cause RTT. MeCP2 is critical for maintaining mature neural networks and postnatal brain development and adult brain. Ward et al. found that patients with RTT syndrome were also associated with urinary dysfunction and renal dysfunction. Mice lacking MeCP2 showed an abnormal pattern of urination, increased frequency of urination, and decreased urination suggesting that MeCP2 may play a role in urinary function.

Relationship Between Mecp2 and Tumor

Mecp2 plays an important role in the epigenetic pathway of tumorigenesis. Mecp2 not only causes neurodevelopmental disorders, but new evidence suggests that MeCP2 is a key oncogene in cancer development. Studies have shown that MeCP2 is present in a variety of tumors. Its targeting gene, MecP2, can affect genes through specific binding to hypermethylated regions. Transcription, inhibition of gene expression, leads to changes in cell proliferation, cell cycle, apoptosis, migration, invasion, and other biological functions that increase the risk of tumorigenesis. It inhibits gene expression mainly in two ways: (1) MeCP2 binds to the methylated CpG residue sequence and attracts Sin3a to form a stable transcriptional repression complex with histone deacetylase (HDAC1 and HDAC2). This complexe can remodel and concentrate chromatin, leading to silencing of gene expression, which is thought to be responsible for long-term silencing of methylation sequences. (2) MeCP2 does not rely on the involvement of HDAcs to compete with transcription factors for binding sites, suggesting that MeCP2 has a wide range of roles in addition to transcriptional repression.

Recently, the use of the anticonvulsant valproic acid has been shown to control the expression of MeCP2 and HDAC1 to HDAC3 genes in C6 glioma cells. Some researchers have explored the expression of MeCP2 in PANC1, PaTu8988, and SW1990 pancreatic cancer cells, and found that down-regulation of MeCP2 expression can inhibit the proliferation and migration of pancreatic cancer cells. Another study also found that MeCP2 is present in four different groups of ovarian tissues, and is significantly higher in the malignant group than in the benign group and the normal group.

References:

Ward, C. S. , Teng-Wei, H. , Herrera José A., Samaco, R. C. , Pitcher, M. R. , & Alan, H. , et al. (2016). Loss of mecp2 causes urological dysfunction and contributes to death by kidney failure in mouse models of rett syndrome. PLOS ONE, 11(11), e0165550-.
Xu-Rui, J. , Xing-Shu, C. , & Lan, X. . (2017). Mecp2 deficiency in neuroglia: new progress in the pathogenesis of rett syndrome. Frontiers in Molecular Neuroscience, 10, 316-.
Tai, D. J. C. , Liu, Y. C. , Hsu, W. L. , Ma, Y. L. , Cheng, S. J. , & Liu, S. Y. , et al. (2016). Mecp2 sumoylation rescues mecp2-mutant-induced behavioural deficits in a mouse model of rett syndrome. Nature Communications, 7, 10552.

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