Mutations in MeCP2, a methyl-CG-binding protein that functions as a regulator of gene expression, are a major cause of Rett syndrome (RTT), an X-linked progressive neurological disorder associated with profound cognitive impairment in girls and women. MECP2 mutations also cause an array of other neurological disorders, including nonsyndromic mental retardation, learning disability, and autism. While the selective inactivation of MeCP2 in neurons has been suggested to be sufficient to confer a Rett-like phenotype in mice, the specific mechanisms by which the loss of MeCP2 function in postmitotic neurons gives rise to RTT pathology remain enigmatic. In preliminary studies we have discovered a subtle, yet consistent genome-wide length-dependent increase in the expression of long genes (>100 kb) in MeCP2-deficient neurons that correlates with phenotypic onset and severity in a variety of RTT models. These MeCP2-regulated long genes encode factors that modulate neuronal physiology, including a number of loci implicated in autism spectrum disorders. Remarkably, the long genes that are misregulated in RTT have a high density of non-CG DNA methylation (mCA) throughout their transcribed regions. Taken together with recent evidence that MeCP2 binds mCA with high affinity, our findings suggest that MeCP2 tempers the expression of long genes in the developing nervous system by binding mCA within their transcribed regions. Moreover, these results suggest that global disruption of the expression of long genes and/or the fidelity of transcription may underlie significant aspects of RTT pathology. To investigate these possibilities and to gain further insight into MeCP2 function in both neural development and RTT etiology, we propose (1) to characterize how non-CG DNA methylation contributes to MeCP2 function, and (2) to investigate the role of neuronal length-dependent gene misregulation in RTT pathophysiology. It is our hope that the proposed experiments will provide a better understanding of MeCP2 function, give insight into RTT etiology, and ultimately provide new opportunities for the development of therapeutic strategies to alleviate RTT pathology.
Rett syndrome is a progressive autistic disorder that is among the most common causes of profound cognitive impairment in girls and women. In an effort to gain insight into the underlying molecular basis of the disorder, the proposed study will seek to explore the hypothesis that this autistic disorder reflects a defect in the dynamic regulation of genes in the central nervous system.
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