Methylated Mouse Model of Fragile X
Abstract
Topic Area: Fragile X Syndrome The neurological disease of Fragile X Syndrome is caused by an unusual mutation in the Fragile X Mental Retardation 1 (FMR1) gene. The mutation, 200 to >1000 copies of a three-nucleotide sequence of DNA (CGG), does not affect the FMR1 protein per se, but instead somehow causes the FMR1 gene to be shut off. The shutting off involves reversible chemical modifications of the DNA called DNA methylation. The cells of patients with Fragile X Syndrome "write" the DNA methylation that shuts off the FMR1 gene. However, certain drugs and newly developed protein systems are able to "erase" the DNA methylation, allowing FMR1 to be turned on again. So far, these promising results have only been obtained in patient cells in a culture dish. An important next step would be to test these DNA methylation-erasing therapies, so-called epigenetic therapies, in a preclinical mouse model of Fragile X Syndrome. Such epigenetic therapies could be an innovative new treatment approach for Fragile X. However, there is a big problem with the existing mouse models of Fragile X Syndrome. Unlike humans, mice with the unusual Fmr1 mutation do not have the DNA methylation, and thus do not shut off the Fmr1 gene. Therefore, existing mouse models cannot be used to test new innovative epigenetic therapies for Fragile X. (There are mouse models in which the Fmr1 gene is shut off due to a genetic mutation made by the investigators; however, these mice are not like the human case and cannot be used to test epigenetic therapies either.) Here we propose an innovative solution to this historic problem. Within the past few years, and the past year in particular, protein-based systems have been developed that can artificially "write" the DNA methylation at any desired gene, causing it to be shut off. In Aim 1 of our project, we will design one of these systems to write the DNA methylation specifically at the mouse Fmr1 gene. In Aim 2, we will create a transgeneic mouse that carries this artificial DNA methylation system. The result will be the first mouse model of Fragile X Syndrome in which the Fmr1 gene is shut off due to DNA methylation, as in the human disease. This will be a critical innovative step that will finally open the door to developing epigenetic therapies for Fragile X. In future work, we will design related systems that, based on the published work of several groups, can erase the DNA methylation at the Fmr1 gene in mouse brain. However, the development of in vivo targetable epigenetic modifiers has important broader implications for other neurologic and neuropsychiatric disorders. Aberrant gene expression is a component of virtually every brain disease, whether due to hemizygosity (e.g., FXS), imprinting (e.g., Rett, Prader-Willi), dominant alleles (e.g., Huntington), haploinsufficiency (e.g., 22q11.2 deletion, Pitt-Hopkins, autism), or experiential stress (e.g., in utero stress, post-traumatic stress). Advances in targetable gene modifications are making it increasingly possible that such aberrant gene expression can be reset in a persistent manner in the brain. Thus, the proposed studies may open new approaches to therapy for such brain disorders including post-traumatic stress disorder (PTSD), an issue of great importance for military personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710200
Entities
People
- David J. Segal
Organizations
- United States Army
- University of California, Davis