RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination

Nuclear processes such as transcription, DNA replication and recombination are dynamically regulated by chromatin structure. Eukaryotic transcription is known to be regulated by chromatin-associated proteins containing conserved protein domains that specifically recognize distinct covalent post- translational modifications on histones. However, it has been unclear whether similar mechanisms are involved in mammalian DNA recombination. Here we show that RAG2 - an essential component of the RAG1/2 V(D)J recombinase, which mediates antigen- receptor gene assembly(1) - contains a plant homeodomain ( PHD) finger that specifically recognizes histone H3 trimethylated at lysine 4 ( H3K4me3). The high- resolution crystal structure of the mouse RAG2 PHD finger bound to H3K4me3 reveals the molecular basis of H3K4me3- recognition by RAG2. Mutations that abrogate RAG2's recognition of H3K4me3 severely impair V( D) J recombination in vivo. Reducing the level of H3K4me3 similarly leads to a decrease in V(D)J recombination in vivo. Notably, a conserved tryptophan residue ( W453) that constitutes a key structural component of the K4me3- binding surface and is essential for RAG2's recognition of H3K4me3 is mutated in patients with immunodeficiency syndromes. Together, our results identify a new function for histone methylation in mammalian DNA recombination. Furthermore, our results provide the first evidence indicating that disrupting the read- out of histone modifications can cause an inherited human disease.