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

Abstract

During the germinal center (GC) reaction, B cells undergo extensive redistribution of cohesin complex and 3D 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, yet in marked contrast Smc3 haploinsufficiency induced GC hyperplasia, skewing of GC polarity and impaired plasma cell differentiation. Genome-wide chromosomal conformation and transcriptional profiling revealed defects in GC B cell terminal differentiation programs controlled by lymphoma epigenetic tumor suppressors Tet2 and Kmt2d, and failure of Smc3wt/– GC B cells to switch from B cell to plasma cell defining transcription factors. Smc3 haploinsufficiency preferentially impaired 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 plasma cell phenotypic switch, while restricting their malignant transformation.