Department of Immunology, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
Nat Commun. 2013;4:1830. doi: 10.1038/ncomms2823.
Somatic hypermutation in B cells is initiated by activation-induced cytidine deaminase-catalyzed C→U deamination at immunoglobulin variable regions. Here we investigate the role of the germinal centre-associated nuclear protein (GANP) in enhancing the access of activation-induced cytidine deaminase (AID) to immunoglobulin variable regions. We show that the nuclear export factor GANP is involved in chromatin modification at rearranged immunoglobulin variable loci, and its activity requires a histone acetyltransferase domain. GANP interacts with the transcription stalling protein Spt5 and facilitates RNA Pol-II recruitment to immunoglobulin variable regions. Germinal centre B cells from ganp-transgenic mice showed a higher AID occupancy at the immunoglobulin variable region, whereas B cells from conditional ganp-knockout mice exhibit a lower AID accessibility. These findings suggest that GANP-mediated chromatin modification promotes transcription complex recruitment and positioning at immunoglobulin variable loci to favour AID targeting.
体细胞超突变是由激活诱导的胞嘧啶脱氨酶催化的免疫球蛋白可变区的 C→U 脱氨作用引发的。在这里，我们研究了生发中心相关核蛋白（GANP）在增强激活诱导的胞嘧啶脱氨酶（AID）进入免疫球蛋白可变区中的作用。我们发现核输出因子 GANP 参与了重排免疫球蛋白可变基因座的染色质修饰，其活性需要组蛋白乙酰转移酶结构域。GANP 与转录停滞蛋白 Spt5 相互作用，并促进 RNA Pol-II 募集到免疫球蛋白可变区。来自 ganp 转基因小鼠的生发中心 B 细胞在免疫球蛋白可变区显示出更高的 AID 占有率，而来自条件性 ganp 敲除小鼠的 B 细胞则显示出更低的 AID 可及性。这些发现表明，GANP 介导的染色质修饰促进了转录复合物在免疫球蛋白可变基因座的募集和定位，从而有利于 AID 的靶向。
