Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Nat Immunol. 2021 Feb;22(2):240-253. doi: 10.1038/s41590-020-00827-8. Epub 2021 Jan 11.
During the germinal center (GC) reaction, B cells undergo extensive redistribution of cohesin complex and three-dimensional reorganization of their genomes. Yet, the significance of cohesin and architectural programming in the humoral immune response is unknown. Herein we report that homozygous deletion of Smc3, encoding the cohesin ATPase subunit, abrogated GC formation, while, in marked contrast, Smc3 haploinsufficiency resulted in GC hyperplasia, skewing of GC polarity and impaired plasma cell (PC) differentiation. Genome-wide chromosomal conformation and transcriptional profiling revealed defects in GC B cell terminal differentiation programs controlled by the lymphoma epigenetic tumor suppressors Tet2 and Kmt2d and failure of Smc3-haploinsufficient GC B cells to switch from B cell- to PC-defining transcription factors. Smc3 haploinsufficiency preferentially impaired the connectivity of enhancer elements controlling various lymphoma tumor suppressor genes, and, accordingly, Smc3 haploinsufficiency accelerated lymphomagenesis in mice with constitutive Bcl6 expression. Collectively, our data indicate a dose-dependent function for cohesin in humoral immunity to facilitate the B cell to PC phenotypic switch while restricting malignant transformation.
在生发中心（GC）反应期间，B 细胞经历广泛的黏合蛋白复合物重分布和基因组的三维重排。然而，黏合蛋白和结构编程在体液免疫反应中的意义尚不清楚。本文报道，编码黏合蛋白 ATP 酶亚基的 Smc3 基因纯合缺失会破坏 GC 的形成，而 Smc3 杂合不足则导致 GC 增生、GC 极性偏斜和浆细胞（PC）分化受损。全基因组染色体构象和转录谱分析显示，由淋巴瘤表观遗传肿瘤抑制因子 Tet2 和 Kmt2d 控制的 GC B 细胞终末分化程序以及 Smc3 杂合不足的 GC B 细胞从 B 细胞到 PC 定义转录因子的转换存在缺陷。Smc3 杂合不足优先损害控制各种淋巴瘤肿瘤抑制基因的增强子元件的连接性，因此，Smc3 杂合不足加速了具有组成性 Bcl6 表达的小鼠的淋巴瘤发生。总之，我们的数据表明黏合蛋白在体液免疫中具有剂量依赖性的功能，可促进 B 细胞向 PC 的表型转换，同时限制恶性转化。
