美国威尔康奈尔医学院Ari M. Melnick课题组发现,Smc3剂量可调节B细胞转变并限制其恶性转化。相关论文于2021年1月11日在线发表于国际学术期刊《自然—免疫学》。
研究人员发现,Smc3的纯合缺失(编码黏连蛋白ATPase亚基)废除了生发中心(GC)的形成,而与此形成鲜明对比的是,Smc3单倍体不足导致GC增生、GC极性倾斜和浆细胞(PC)分化受损。全基因组染色体构象和转录谱揭示了由淋巴瘤表观遗传抑制因子Tet2和Kmt2d控制的GC B细胞末端分化程序的缺陷,以及Smc3-单倍型不足的GC B细胞无法从B细胞转换为PC的转录因子。Smc3单倍体不足会优先损害控制各种淋巴瘤抑癌基因的增强子的连通性,因此,Smc3单倍体不足会加速具有组成型Bcl6表达小鼠的淋巴瘤发生。
总体而言,这些数据表明黏连蛋白在体液免疫中具有剂量依赖性功能,从而促进B细胞向PC表型转换,同时限制恶性转化。
据悉,在GC反应过程中,B细胞经历了黏连蛋白复合物的广泛再分布和其基因组的三维重组。然而,在体内免疫应答中黏连蛋白和结构化程序的重要性尚不清楚。
附:英文原文
Title: Smc3 dosage regulates B cell transit through germinal centers and restricts their malignant transformation
Author: Martn A. Rivas, Cem Meydan, Christopher R. Chin, Matt F. Challman, Daleum Kim, Bhavneet Bhinder, Andreas Kloetgen, Aaron D. Viny, Matt R. Teater, Dylan R. McNally, Ashley S. Doane, Wendy Bguelin, Mara Teresa Calvo Fernndez, Hao Shen, Xiang Wang, Ross L. Levine, Zhengming Chen, Aristotelis Tsirigos, Olivier Elemento, Christopher E. Mason, Ari M. Melnick
Issue&Volume: 2021-01-11
Abstract: 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. Melnick and colleagues show that the cohesin complex exhibits dose-dependent regulation of chromatin remodeling that accompanies the transition of germinal center B cells to plasma cells, which is necessary to prevent lymphomagenesis.
DOI: 10.1038/s41590-020-00827-8
Source: https://www.nature.com/articles/s41590-020-00827-8
Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex