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Research Paper
Spatio-temporal Dynamics and Localization of MeCP2 and Pathological Mutants in Living Cells
Matilde Marchi, Alessia Guarda, Anna Bergo, Nicoletta Landsberger, Charlotte Kilstrup-Nielsen, Gian Michele Ratto and Mario Costa
volume 2 | issue 3
july/august/september 2007Subscribe to this journal for $79/year
MECP2 is an X-linked gene coding for a protein functioning as a transcriptional repressor. The protein MeCP2 (Methyl CpG–binding protein) is an abundant component of pericentric heterochromatin and its mutations or duplications are present in around 80% of patients with a neurological disorder known as Rett Syndrome. Although MeCP2 action depends critically on its binding to chromatin, very little is known about the dynamics of this process. Using fluorescence recovery after photobleaching in controlled conditions of protein concentration, we demonstrate that most of the GFP-MeCP2 fusion protein associates strongly and reversibly to pericentric heterocromatin whereas the remaining fraction is bound irreversibly. The mobility of the methyl-binding protein is influenced by the differentiation state of the host cells. Furthermore, residues downstream of the methyl-binding domain are critical for the interaction with chromatin. Whereas the binding is stabilised by the central region it is likely modulated by the most C-terminal region. Importantly, these residues are missing in several disease causing mutations. Our data suggest that alterations in the affinity of MeCP2 for chromatin might contribute to the pathological effects of mutations causing Rett Syndrome.
Authors
Matilde Marchi
Italian Institute of Technology (IIT); NEST, Scuola Normale Superiore
Alessia Guarda
University of Insubria
Anna Bergo
University of Insubria
Nicoletta Landsberger
University of Insubria
Charlotte Kilstrup-Nielsen
University of Insubria
Gian Michele Ratto
Institute of Neuroscience, Italian National Research Council (CNR); NEST, Scuola Normale Superiore
Mario Costa
Institute of Neuroscience, Italian National Research Council (CNR)