DNA Methylation, MeCP2 and Rett Syndrome

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DNA Methylation, MeCP2 and Rett Syndrome

Methylation of DNA is an essential component of genomic signalling. One way of reading the signal involves proteins that only interaction with the genome when their binding site is methylated. The best-studied such protein is MeCP2, which in neurons is almost as abundant as the histone proteins that ubiquitously package DNA. MeCP2-deficiency leads to serious neurological disorders, in particular the autism spectrum-like disorder Rett Syndrome. Due to its monogenic origin, Rett Syndrome has become one of the most experimentally accessible examples of such neurological conditions and this offers a golden opportunity to understand its complex pathology at a molecular level. Our mouse model of Rett Syndrome has greatly improved understanding of this disorder, in particular by demonstrating that advanced Rett-like symptoms in mice can be “cured” by putting back a functional MeCP2 gene.

Current projects, funded by Wellcome Investigator Award, are designed to probe MeCP2 function more deeply, particularly its involvement with partner proteins and its role in controlling gene expression. In addition, we are pursuing gene editing approaches that target specific Rett syndrome mutations as a prelude to developing novel therapies.

The influence of DNA base composition on chromatin modification and gene expression

This research programme, initially funded by an Advanced Grant from the European Research Council, explores the possibility that the genomic sequence itself is a major contributor to epigenetic conditioning that stabilizes gene expression programmes. Specifically, we ask whether transcription patterns that define cell states are determined by transcription factors that recognise short or highly redundant DNA recognition sequences. Validating the hypothesis, we found that in stem cells SALL4 binds preferentially to genes embedded in AT-rich regions of the genome in order to prevent precocious differentiation. Thus, SALL4 is able to interpret DNA base composition as a signal to stabilise the stem cell state.

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European Research Council

Our current projects are designed to expand knowledge of the molecular mechanisms at work in the case of SALL4 and related proteins. Furthermore, we are screening for novel base composition readers that may operate in an analogous way.

Are the genetic causes of autism convergent?

The Simons Initiative for the Developing Brain is dedicated to improving our knowledge of autism in order to help develop therapies. At first sight, the large number of mutated genes that have been causally implicated in autism is disappointing, as it suggests that multiple independent molecular processes are at work, each requiring a different therapeutic approach. A more optimistic view is that many autism genes affect a relatively small number of common molecular pathways, which would simplify the search for treatments. Current projects within my lab are testing for “convergence” among proteins that affect chromatin structure and function.

Simons Initiative for the Developing Brain

To gain further insight into our mouse model for the reversal of Rett Syndrome, please watch the videos below. The first shows a mouse deficient in the protein MeCP2 exhibiting Rett-like symptoms. The second shows the recovery of the same mouse shown in the first video after MeCP2 has been restored (taken from Guy et al, Science 2007).