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Science 30 May 2008:
Vol. 320. no. 5880, pp. 1224 - 1229
DOI: 10.1126/science.1153252
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Reports

MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription

Maria Chahrour,1 Sung Yun Jung,2 Chad Shaw,1 Xiaobo Zhou,3 Stephen T. C. Wong,3 Jun Qin,2,4 Huda Y. Zoghbi1,5,6,7,8*

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (~85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2 Center for Molecular Discovery, Departments of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
3 Center for Bioinformatics, The Methodist Hospital Research Institute and Weill Cornell College of Medicine, Houston, TX 77030, USA.
4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
5 Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
6 Departments of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
7 Programs in Cell and Molecular Biology and Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
8 Howard Hughes Medical Institute, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: hzoghbi{at}bcm.edu

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