So, Freddy sent me a thesis written in 2006 from a German University. It is about a methyl CpG binding protein, called MeCP2, that suppresses GR-target genes. MeCP2 has been shown to be required for the normal function of neurons and is usually thought to act as a repressor of genes, including CRH (my favorite gene). Mutations in the MECP2 gene has been strongly linked to a neurodevelopmental disorder known as Rett Syndrome.
In this paper, they used a microarray analysis to compare gene expression from WT and MeCP2-null mice. They discovered that at least 5 of the 11 differentially regulated genes are GR target genes. They show by ChIP (your favorite technique!) that MeCP2 binds to the promoter region of FKBP5 and SGK1, suggesting a relationship between MeCP2 occupancy and gene expression. Its not very clear to me in the paper, but what is really novel in the thesis is that Dex prevents Mecp2 from binding to a GRE within the FKBP5 gene. This is prevented by RU486. Its in the last figure of the RESULTS Section found HERE.
The bigger picture here, I think, is how epigenetics, in particular, DNA methylation, is regulating the expression of these GR target genes in neurons. This has many implications for stress response since one of the identified genes, POMC, is a key player of the HPA axis and CRH also has been shown to be regulated by MeCP2.
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This paper, as well as Freddie’s thesis, make nice arguments that glucocorticoid signaling, in the absence of MeCP2, may contribute to Rett’s syndrome. The increased basal BDNF expression in the neurons of Rett’s syndrome mice may enhance any GR mediated effects. Since the authors administered corticosterone to MeCP2 WT and KO mice and observed changes in Sgk1 and Fkbp5 gene expression, it would have been interesting to see if treatment with RU486 lowered gene expression and/or lessened the Rett’s phenotype. It will also be interesting to see which phosphorylated form of GR bumps MeCP2 off target promoters and which kinases promote this phophorylation as potential therapies for Rett’s patients.
ReplyDeleteIncreased expression of some GR target genes in MeCP2-null mice supports the involvement of GR signaling in Rett syndrom. However, how MeCP2 and GR affect each other is not fully revealed. This paper showed no effect by corticosterone on MeCP2 binding to the tested DNA sites, whereas the thesis data demonstrated a competition between MeCP2 and GR on a GRE, suggesting not all the MeCP2 binding sites are important in regulation by GR.
ReplyDelete@Natalie- Its interesting that you noted that the increased BDNF expression may be enhancing GR mediated effects since we've shown that SGK gene expression is enhanced upon BDNF and Dex treatment. I agree, too, that they could have futhered the experiments with RU486 to see if it actually affected the Rett phenotype. Good point. I think this GR-MECP2 occupancy of the same region is very novel and suggests that their maybe a physical interaction but that has yet to be proven. In the event there is, phospho-forms of GR may very well be integral in this dynamic interaction.
ReplyDelete@Chaowei- I'd be also interested to know how MeCP2 interacts with other transcription factors like CREB for example. There is a methylated CpG site in the CRE of the CRH gene. Is a similar mechanism employed here? It may not have come up in the screen because it could be cell-type specific.