Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin.

Journal article

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: Eustermann, S; Yang, J; Law, M; Amos, R; Chapman, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Publishing Group
• Journal: Nature structural and molecular biology
• Volume: 18
• Issue: 7
• Pages: 777-782
• Publication date: 2011-01-01
• DOI: 10.1038/nsmb.2070
• EISSN: 1545-9985
• ISSN: 1545-9993
• Language: English
• Keywords: Chromosomal Proteins, Non-Histone; Chromatin Assembly and Disassembly; Methylation; Binding Sites; DNA Helicases; Nuclear Magnetic Resonance, Biomolecular; Histone Code; Heterochromatin; Histones; Nuclear Proteins