PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here we show that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3) /MLL4 complex display impaired histone methylation (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus leading to defective immunoglobulin class-switching. We also show that PTIP accumulation at DSBs contributes to class-switch recombination (CSR) and genome stability independently from Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR, and suggest a non-redundant role for the MLL3/MLL4 complex in altering antibody effector function.

淋巴细胞的程序性基因重排，需依赖抗原受体基因的转录，以提升双链断裂（double-strand break, DSB）形成的可及性——该断裂对于DNA重组与修复至关重要。本研究显示，携带MLL3（mixed-lineage leukemia 3，混合谱系白血病3）/MLL4复合物PTIP亚基缺陷的活化B细胞，其组蛋白甲基化（H3K4me3）水平以及免疫球蛋白重链（Igh）基因座下游转换区的转录起始过程均受损，进而引发免疫球蛋白类别转换缺陷。我们同时证实，PTIP在双链断裂处的聚集，可独立于Igh转换区转录之外，参与类别转换重组（class-switch recombination, CSR）过程并维持基因组稳定性。上述结果表明，PTIP可通过调控特定染色质改变，控制Igh基因座对CSR的可及性；同时提示MLL3/MLL4复合物在调控抗体效应功能方面具备非冗余的重要作用。