CFP1 promotes germinal center affinity maturation and restrains memory B cell differentiation through H3K4me3 modulation

Yanan Zhao, Shuoxu Gong, Yalin Yang, Yimiao Lu, Jingning Bai, Meiling Liu, Wanyu Bai () and Junchao Dong ()
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Yanan Zhao: Sun Yat-sen University
Shuoxu Gong: Sun Yat-sen University
Yalin Yang: The Seventh Affiliated Hospital of Sun Yat-Sen University
Yimiao Lu: Sun Yat-sen University
Jingning Bai: Sun Yat-sen University
Meiling Liu: Sun Yat-sen University
Wanyu Bai: Sun Yat-sen University
Junchao Dong: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Affinity maturation and differentiation of B cells in the germinal center (GC) are tightly controlled by epigenetically regulated transcription programs, but the underlying mechanisms are only partially understood. Here we show that Cfp1, an integral component of the histone methyltransferase complex Setd1A/B, is critically required for GC responses. Cfp1 deficiency in activated B cells greatly impairs GC formation with diminished proliferation, somatic hypermutation and affinity maturation. Mechanistically, Cfp1 deletion reduces H3K4me3 marks at a subset of cell cycle and GC-related genes and impairs their transcription. Importantly, Cfp1 promotes the expression of transcription factors MEF2B and OCA-B and the Bcl6 enhancer-promoter looping for its efficient induction. Accordingly, Cfp1-deficient GCB cells upregulate IRF4 and preferentially differentiate into plasmablasts. Furthermore, Cfp1 ablation upregulates a panel of pre-memory genes with elevated H3K4me3 and leads to markedly expanded memory B populations. In summary, our study reveals that Cfp1-safeguarded epigenetic regulation ensures proper dynamics of GCB cells for affinity maturation and prevents the pre-mature exit from GC as memory cells.

Date: 2025
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DOI: 10.1038/s41467-025-63291-8

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