Many genetic disorders are characterized by defects in neuronal function and cognitive ability. To gainkey insights into new ways of approaching these diseases, it is critical to understand the molecularbasis for regulating neuronal transcriptional programs and take advantage of emerging globalgenomic technologies, which provide deep insights into the molecular basis for these disorders. Here,we focus on a severe neurological disorder that is caused by mutations of the methyl-CpG-bindingprotein, MeCP2, and how it causes alterations in gene expression programs required for neuronalfunction. We propose to investigate this perplexing syndrome, which can be categorized under theumbrella of “autism spectrum” disorders, to test a previously unappreciated mechanism for regulatingneuronal transcription programs based on chromosomal architecture. Specifically, we will determinethe effects of MeCP2 loss on chromatin architecture and its relation to changes in gene transcription,as well as determine the functional role of MeCP2 on the nuclear matrix-dependent architecturalnetwork. We will utilize several mouse genetic models to target several important brain cell types andapply genome wide methodologies to elucidate the contribution of each of these to the observed brainphenotype. We expect to expand our understanding of MeCP2-dependent transcriptional de-regulation due to structural effects on chromosome architecture, and uncover the role of MeCP2 inregulation of chromosomal boundary/ sub-nuclear architectural interactions as an underlyingmechanism in Rett syndrome. This will enable new understanding of the molecular mechanisms ofthis devastating neurological disease, and lay the groundwork for potential new classes of potentialtherapeutic avenues.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
