title: MeCP2 Rett mutations affect large scale chromatin organization.
abstract: 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.
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Noopur
authors.initials: N
authors.lastname: Agarwal
authors.forename: Annette
authors.initials: A
authors.lastname: Becker
authors.forename: K Laurence
authors.initials: KL
authors.lastname: Jost
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haase
authors.forename: Basant K
authors.initials: BK
authors.lastname: Thakur
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brero
authors.forename: Tanja
authors.initials: T
authors.lastname: Hardt
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kudo
authors.forename: Heinrich
authors.initials: H
authors.lastname: Leonhardt
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Cardoso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D016000:Cluster Analysis; D006801:Humans; D007700:Kinetics; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics*
chemical_list: D002843:Chromatin; D051783:Methyl-CpG-Binding Protein 2; D050505:Mutant Proteins