Journal Article

MeCP2 Rett mutations affect large scale chromatin organization

Noopur Agarwal, Annette Becker, K. Laurence Jost, Sebastian Haase, Basant K. Thakur, Alessandro Brero, Tanja Hardt, Shinichi Kudo, Heinrich Leonhardt and M. Cristina Cardoso

in Human Molecular Genetics

Volume 20, issue 21, pages 4187-4195
Published in print November 2011 | ISSN: 0964-6906
Published online August 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr346
MeCP2 Rett mutations affect large scale chromatin organization

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Rett syndrome is a neurological, X chromosomal-linked disorder associated with mutations in the MECP2 gene. MeCP2 protein has been proposed to play a role in transcriptional regulation as well as in chromatin architecture. Since MeCP2 mutant cells exhibit surprisingly mild changes in gene expression, we have now explored the possibility that Rett mutations may affect the ability of MeCP2 to bind and organize chromatin. We found that all but one of the 21 missense MeCP2 mutants analyzed accumulated at heterochromatin and about half of them were significantly affected. Furthermore, two-thirds of all mutants showed a significantly decreased ability to cluster heterochromatin. Three mutants containing different proline substitutions (P101H, P101R and P152R) were severely affected only in heterochromatin clustering and located far away from the DNA interface in the MeCP2 methyl-binding domain structure. MeCP2 mutants affected in heterochromatin accumulation further exhibited the shortest residence time on heterochromatin, followed by intermediate binding kinetics for clustering impaired mutants. We propose that different interactions of MeCP2 with methyl cytosines, DNA and likely other heterochromatin proteins are required for MeCP2 function and their dysfunction lead to Rett syndrome.

Journal Article.  4392 words.  Illustrated.

Subjects: Genetics and Genomics

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