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Human Molecular Genetics Advance Access published online on April 13, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl099
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received February 17, 2006
Revised April 5, 2006
Accepted April 5, 2006

Article

Identification of cis-regulatory elements for MECP2 expression

Jinglan Liu 1 and Uta Francke 2 *

1 Departments of Genetics, Stanford University School of Medicine, Stanford, CA, USA
2 Departments of Genetics, Stanford University School of Medicine, Beckman Center for Molecular and Genetic Medicine, 279 Campus Drive, Stanford, CA 94305-5323, USA; Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

* To whom correspondence should be addressed.
Uta Francke, E-mail: ufrancke{at}stanford.edu


  Abstract

Rett syndrome (RTT) is an X-linked dominant disabling neurodevelopmental disorder caused by loss of function mutations in the MECP2 gene, located at Xq28, which encodes a multifunctional protein. MECP2 expression is regulated in a developmental stage and cell-type specific manner. The need for tightly controlled MeCP2 levels in brain is strongly suggested by neurologically abnormal phenotypes of mouse models with mild overexpression, and by mental retardation in human males with MECP2 duplication. We set out to identify long-range cis-regulatory sequences that differentially regulate MECP2 transcription, and when mutated, may contribute to the pathogenesis of RTT, autism or X-linked mental retardation. By inter-species sequence comparisons we detected 27 highly conserved non-coding DNA sequences within a 210 kb region covering MECP2. We functionally confirmed four enhancer and two silencer elements by performing luciferase reporter assays in four different human cell lines. The transcription factor binding capability of the identified regulatory elements was tested by gel shift assays. To locate the human MECP2 core promoter, we dissected the promoter region by reporter assays with deletion constructs. We then used chromosome conformation capture methods to document long-range interactions of three enhancers and two silencers with the MECP2 promoter. Acting over distances of up to 130 kb, these elements may influence chromatin configurations and regulate MECP2 transcription. Our study has defined the "MECP2 functional expression module" and identified enhancer and silencer elements that are likely to be responsible for the tissue-specific, developmental stage-specific or splice-variant specific control of MeCP2 protein expression.


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