Stimulation of V(D)J recombination by histone acetylation.
V(D)J recombination assembles functional immunoglobulin and T cell receptor genes from individual gene segments [1]. A common recombination mechanism, initiated by the proteins RAG1 and RAG2 at conserved recombination signal sequences (RSSs), operates at all rearranging loci [2] [3]. It has been proposed that the key regulator of the reaction is 'accessibility' of the RSS within chromatin [4]. Recently, the packaging of RSSs into nucleosomes was shown to inhibit initiation of V(D)J recombination [5] [6]. Nevertheless, the tight tissue specificity of regulation cannot be explained by nucleosome-mediated repression alone because a significant fraction of RSSs would be predicted to lie in linker regions between nucleosomes. Therefore, some aspect of the regulation of the recombination reaction must rely on the disruption of higher-order chromatin structure. Here, we report that histone acetylation directly stimulates the recombination reaction in vivo in the correct cell- and stage-specific manner. Neither expression of RAG genes nor activity of RAG proteins was increased by acetylation. Furthermore, histone acetylation failed to overcome nucleosome-mediated repression of RSS recognition and cleavage in vitro. Our data suggest a role for histone acetylation in stimulating recombination in vivo through disruption of higher-order chromatin structures.
McBlane
F
F
Basel Institute for Immunology, Basel, CH-4005, Switzerland. mcblane@bii.ch
Boyes
J
J
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D004254:DNA Nucleotidyltransferases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015321:Gene Rearrangement / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D045567:VDJ Recombinases
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; D007145:Immunoglobulin kappa-Chains; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; C012589:trichostatin A; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases