Understanding Neuronal Dysfunction in Rett Syndrome
Primary or secondary abnormalities of epigenetic regulation are found in several human diseases including neurodevelopmental disorders, neurodegeneration, and cancer. It is well established that DNA methylation patterns are highly regulated during development and that disruption of epigenetic marks can lead to a number of cellular abnormalities. How environmental factors affect DNA methylation and gene expression however is less well understood. Folic acid is essential for DNA methylation, a modification required for the recruitment of methyl-CpG DNA binding proteins to chromatin, including Mecp2, the product of the gene mutated in Rett syndrome.
We have shown that methyl donors modify growth, motor function and survival in Mecp2 mutant mice and that these mice have phenotypic and molecular evidence of hypothalamic dysfunction. We identified expression changes in the mouse hypothalamus in response to:
- changes in dietary methyl donors,
- mutation of Mecp2, or
- an interaction between these genetic and dietary factors.
These genes are relevant to our understanding of the role of DNA methylation in brain function and the identification of epigenetic pathways sensitive to environmental changes. The human orthologs of 14% of these genes are known to contain mutations causing mendelian disorders.
We are investigating the relative contribution of methyl donors and genes involved in the control of DNA methylation in the regulation of brain function. As a genetic tool, we are using mice carrying inducible mutations of DNA methyltransferases or methyl CpG DNA binding proteins.
We hypothesize that environmental factors play an important role in the modulation of epigenetic marks in neurons, especially in subcortical structures of the brain devoted to regulating physiology and behavior in response to the environment. Specifically, this work will test the following two hypotheses:
- Disruption of DNA methylation restricted to hypothalamic arcuate neurons is sufficient to reproduce critical features of Rett syndrome including hypothalamic dysfunction and misexpression of Pomc, Npy, and Agrp;
- Mutation of Mecp2 or DNA methyltransferase genes and dietary methyl donors interact to modulate gene expression and chromatin structure in the arcuate neurons of the hypothalamus. The long-term goal of our project is the dissection of genetic factors, environmental manipulations and gene-environment interactions critical to the regulation of DNA methylation in neurons and the development of epigenetic treatment strategies for neurological diseases with primary or secondary abnormalities of epigenetic regulation.
Relevance of the project to IDDRC mission:
Our project has direct relevance to the mission of the IDDRC. Several neurological diseases including autism, mental retardation and neurodegenerative disorders are clearly complex and heterogeneous and have both genetic and environmental causes.
Our studies aim to identify disease pathways in the brain that are sensitive to environmental manipulations of the epigenome, and to dissect the mechanisms of these effects. We believe that these studies could lead to either preventative or therapeutic manipulations in a number of neurological disorders with primary or secondary abnormalities of epigenetic regulation.