RETT syndrome

> Cette page en françaisRettMecp2fonction_fr.html
HOMEAccueil_gb.html
RETTRett1_gb.html
EPILEPSIESEpilepsies1_gb.html
CONTACTContact_gb.html
OUR TEAMEquipe1_gb.html
NEWSNews1_gb.html
LINKSLiens_gb.html
 

THE FUNCTION OF MECP2

Functional studies conducted using the mouse Mecp2 protein lead to important findings. MeCP2 is a member of the family of proteins able to bind to methylated DNA on CpG dinucleotides. These dinucleotides are largely distributed in the mammalian genomes but they are enriched in regions which are transcriptionnally silent (heterochromatin) and in the promotor region of many genes. Approximately 60% of cytosines located in CpG pairs are methylated. This constitutes an essential mechanism to repress transcription both in the heterochromatin and in regions which are transiently repressed. Methylation itself is not suffucient to repress the expression of a gene. It was demonstrated that the onset of repression is possible because additional proteins are recruited at these methylated sites. For a review, see Ulrey et al., 2004.

The MeCP2 protein contains two functional domains : a methyl binding domains (MBD) which binds methylated CpG dinucleotides, and a transcriptional repression domain (TRD) (Nan et al., 1993 ; Nan et al., 1998).

Co-immunoprecipitation experiments showed that MeCP2 is associated, in mice, with several other proteins such as Sin3A (a transcriptional co-repressor) and the histone deacetylases HDAC1 and HDAC2. MeCP2 would promote transcriptional repression through its binding to CpG dinucleotides and its subsequent recruitment of histone deacetylases that would modify the chromatin structure to make it inactive (this mechanism is presented below).

silencing

MECP2

Sin3A

HDAC

methyl group

X

gene

A search for targets of the MeCP2 protein did not allow to detect massive deregulation of gene transcription when the MeCP2 gene product is absent. This absence of "global" modification of transcriptional activity in the affected cells is partly contradictory with the proposed role of this protein.


In 2005 a slightly different mechanism was proposed (Horike et al., 2005). Indeed, the MeCP2 protein could repress transcription via the formation of inactive DNA loops rather than a via direct repression like the mechanism proposed in the figure above. The role of the MeCP2 protein would thus be less simple than initially anticipated (binding upstream elements and silencing downstream genes). The protein could be able to recognize specific DNA sequences and would promote the creation of loops between these regions. The consequence would be the silencing of the genes contained inside the loops. One interesting point (in addition to the discovery of this alternative function) is that one such loop contains the Dlx5 gene. Dlx5 is important for the neurotransmitter GABA to be synthetized. A first draft is thus maybe appearing linking MeCP2, inactive DNA loops, Dlx5 and neurones (via GABA). These two mechanisms are not necessarily mutually exclusive. A review on the subject can be found here (Chadwick et Wade, 2007).


More recently, the laboratory of Adrian Bird demonstrated that the Mecp2 protein is widely distributed in nucleus of post-mitotic neurons where it could modulate gene expression by replacing the «linker» histone H1. According to this model, Mecp2 would have the ability to globally modulate the expression of the genome of a neuronal cell through a modification of its chromatin architecture (Skene et al. 2010).

The question of the exact function of the Mecp2 protein remains...

«DNA loops» are localy silenced

(according to Horike et al. 2005)

Modification of chromatin structure (replacement of histone H1, in yellow)

(according to Skene et al. 2010)