A number of teams have already spent time in trying to uncover the path that leads from MeCP2 disruption to Rett syndrome, a severe neurodevelopmental disorder in the autism spectrum. Adding detail to MeCP2’s repressive function, a team led by Michael Greenberg gathered data from MeCP2 mouse mutants and patient samples, finding an unexpected clue in long-gene transcription.
When it comes to MeCP2’s function researchers are divided. One school of thought suggests that it is a traditional transcriptional repressor, but another suggests a much more context dependent regulation, similar to that of a histone mod, enabled by alternative splicing and post-translational modifications, where it can interact with active genes. Interestingly, a previous study lead by Rudolf Jaenisch and lab at the Whitehead Institute for Biomedical Research (Cambridge, USA) showed that MECP2 functions as a global activator in neurons but not in neural precursors, which was done using TALEN genome editing.
Now in this recent report Greenberg’s team discovered that, in both mouse models and patient samples, long genes are upregulated, while if MeCP2 is overexpressed these genes are downregulated.
In order to understand how this plays a role in Rett syndrome the team started out from the well-set trail mark of MeCP2 binding to methylated cytosines (5mC). From analysis of this they discovered, like any good hiker, MeCP2 doesn’t travel long routes by itself, preferring the company of mCpG duos, although it can also bind to mCH duos and 5hmCH too, where H is prevalently an A.
Traveling further down the trail the authors uncovered:
- MeCP2 favors long genes, where 5mCA levels are high, which they determined using ChIP.
- Long genes, rich in 5mCA, are upregulated in MeCP2 knockouts and in Rett patients samples.
- Short genes are not affected, even if they display high 5mCA density.
- 5mCA in the brain is mostly located on long genes, implying a specific mode of regulation.
- Moreover, knocking out Dnmt3a results in a reduction in 5mCA levels and a similar misregulation as that in MeCP2 knockout mice.
- Generally, the long genes repressed by MeCP2 encode for neuronal functions and are expressed primarily within the brain.
- However, there wasn’t only one direction of deregulation, many genes are not just induced but also repressed when MeCP2 is gone but their common features remain more of a mystery in the long-gene context.
- Interestingly, another protein, FMRP, which is inactivated in fragile X syndrome and represses mRNA translation, is found to target long genes similar to those targeted by MeCP2.
The long genes road may lead to a solution to treat Rett syndrome patients, through the use of topoisomerase inhibitors that might reverse the observed gene upregulation. The authors take the first steps by treating MeCP2-deficient neurons and obtaining a dose-dependent reversion of the Rett phenotype.
Why not take a look at the full article? Just grab your boots and take the long walk over to Nature, March 2015.