Nucleic Acids Research: VOLUME 37 ISSUE 19 2009

Targeted chromatin remodelling is essential for many nuclear processes, including the regulation of V(D)J recombination. ATP-dependent nucleosome remodelling complexes are important players in this process whose activity must be tightly regulated. We show here that histone acetylation regulates nucleosome remodelling complex activity to boost RAG cutting during the initiation of V(D)J recombination. RAG cutting requires nucleosome mobilization from recombination signal sequences. Histone acetylation does not stimulate nucleosome mobilization per se by CHRAC, ACF or their catalytic subunit, ISWI. Instead, we find the more open structure of acetylated chromatin regulates the ability of nucleosome remodelling complexes to access their nucleosome templates. We also find that bromodomain/acetylated histone tail interactions can contribute to this targeting at limited concentrations of remodelling complex. We therefore propose that the changes in higher order chromatin structure associated with histone acetylation contribute to the correct targeting of nucleosome remodelling complexes and this is a novel way in which histone acetylation can modulate remodelling complex activity. INTRODUCTION The highly condensed chromatin structure in the eukaryotic nucleus provides a formidable obstacle to prevent protein access to DNA. A fundamental question is how different regulatory elements co-operate to ensure that this chromatin packaging is disrupted only at specific loci in the appropriate cell type. One important group of players in this process is ATP-dependent nucleosome remodelling complexes. These complexes increase the accessibility of proteins to nucleosomal DNA by one of the several mechanisms: Sliding the histone octamer along the DNA template, localized disruption of histone/DNA contacts or trans-displacement of the histone octamer (1,2). Since these complexes function in an energy-dependent manner and play important roles in controlling the accessibility of DNA sequences, their activity needs to be tightly regulated. During gene activation, remodelling complexes can be targeted to promoters via their association with transcriptional activators. For example, SWI/SNF is known to associate with acidic activators, such as Swi5, Gcn4 and Hap4 (3,4). A second potential means of targeting remodelling complexes is via interaction between specific domains, found in some subunits of remodelling complexes, and modified histone tails. For example, between bromodomains and acetylated histone tails as well as between PHD fingers and histone H3 trimethylated at lysine 4 (5). Indeed, the bromodomain in the Swi2/Snf2 Present address: Matthias Baumann, GPC Biotech AG, D-82152 Martinsried, Germany. The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. *To whom correspondence should be addressed. Tel: 44 113 343 3147; Fax: 44 113 343 3167; Email: J.M.Boyes@leeds.ac.uk