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

doi:10.1126/science.1153252

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

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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 repressormethyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmentaldisorder Rett syndrome. Loss of function as well as increaseddosage 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 ofmice that either lack or overexpress MeCP2. In both models,MeCP2 dysfunction induced changes in the expression levels ofthousands of genes, but unexpectedly the majority of genes ( $~$ 85%)appeared to be activated by MeCP2. We selected six genes andconfirmed that MeCP2 binds to their promoters. Furthermore,we showed that MeCP2 associates with the transcriptional activatorCREB1 at the promoter of an activated target but not a repressedtarget. These studies suggest that MeCP2 regulates the expressionof a wide range of genes in the hypothalamus and that it canfunction 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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