title: Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin.
abstract: Accurate read-out of chromatin modifications is essential for eukaryotic life. Mutations in the gene encoding X-linked ATRX protein cause a mental-retardation syndrome, whereas wild-type ATRX protein targets pericentric and telomeric heterochromatin for deposition of the histone variant H3.3 by means of a largely unknown mechanism. Here we show that the ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. In vivo experiments show this combinatorial readout is required for ATRX localization, with recruitment enhanced by a third interaction through heterochromatin protein-1 (HP1) that also recognizes trimethylated Lys9. The cooperation of ATRX ADD domain and HP1 in chromatin recruitment results in a tripartite interaction that may span neighboring nucleosomes and illustrates how the 'histone-code' is interpreted by a combination of multivalent effector-chromatin interactions.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Eustermann
authors.forename: Ji-Chun
authors.initials: JC
authors.lastname: Yang
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Law
authors.forename: Rachel
authors.initials: R
authors.lastname: Amos
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Chapman
authors.forename: Clare
authors.initials: C
authors.lastname: Jelinska
authors.forename: David
authors.initials: D
authors.lastname: Garrick
authors.forename: David
authors.initials: D
authors.lastname: Clynes
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
authors.forename: Daniela
authors.initials: D
authors.lastname: Rhodes
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: David
authors.initials: D
authors.lastname: Neuhaus
mesh_terms: D001665:Binding Sites; D042002:Chromatin Assembly and Disassembly; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism*; D042421:Histone Code; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D000075924:X-linked Nuclear Protein
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins; D000090266:Chromobox Protein Homolog 5; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein