Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de Santé et de Recherche Médicale Unité 964/Centre National de Recherche Scientifique Unité Mixte de Recherche 7104, Université de Strasbourg, 67404 Illkirch, France.
J Exp Med. 2011 Aug 1;208(8):1649-60. doi: 10.1084/jem.20110118. Epub 2011 Jul 11.
Immunoglobulin class switch recombination (CSR) is initiated by double-stranded DNA breaks (DSBs) in switch regions triggered by activation-induced cytidine deaminase (AID). Although CSR correlates with epigenetic modifications at the IgH locus, the relationship between these modifications and AID remains unknown. In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain-associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (Sμ) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to Sμ, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR.
免疫球蛋白类别转换重组（CSR）是由激活诱导胞嘧啶脱氨酶（AID）触发的开关区域中的双链 DNA 断裂（DSB）引发的。尽管 CSR 与 IgH 基因座上的表观遗传修饰相关，但这些修饰与 AID 之间的关系尚不清楚。在这项研究中，我们表明，在 CSR 过程中，AID 与 KAP1（KRAB 结构域相关蛋白 1）和 HP1（异染色质蛋白 1）形成复合物，该复合物与携带 H3K9me3（组蛋白 H3 在赖氨酸 9 上的三甲基化）的供体开关区（Sμ）相连在体内。此外，体内破坏该复合物会导致 AID 向 Sμ 的募集受损、DSB 形成效率降低以及 CSR 伴随缺陷，但体细胞高频突变不受影响。我们提出 KAP1 和 HP1 将 AID 固定在供体开关区的 H3K9me3 残基上，从而提供了一种将 AID 与 CSR 过程中的表观遗传修饰联系起来的机制。
