Smc3 dosage regulates B cell transit through germinal centers and restricts their malignant transformation.

Nature immunology 2021 Feb

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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.

Citation

Martín 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 Béguelin, María Teresa Calvo Fernández, Hao Shen, Xiang Wang, Ross L Levine, Zhengming Chen, Aristotelis Tsirigos, Olivier Elemento, Christopher E Mason, Ari M Melnick. Smc3 dosage regulates B cell transit through germinal centers and restricts their malignant transformation. Nature immunology. 2021 Feb;22(2):240-253