Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells

Clara Cousu, Eléonore Mulot, Annie Smet, Sara Formichetti, Damiana Lecoeuche, Jianke Ren, Kathrin Muegge, Matthieu Boulard, Jean-Claude Weill, Claude-Agnès Reynaud and Sébastien Storck ()
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Clara Cousu: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Eléonore Mulot: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Annie Smet: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Sara Formichetti: Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL)
Damiana Lecoeuche: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Jianke Ren: National Cancer Institute
Kathrin Muegge: National Cancer Institute
Matthieu Boulard: Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL)
Jean-Claude Weill: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Claude-Agnès Reynaud: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades
Sébastien Storck: Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract HELLS/LSH (Helicase, Lymphoid Specific) is a SNF2-like chromatin remodelling protein involved in DNA methylation. Its loss-of-function in humans causes humoral immunodeficiency, called ICF4 syndrome (Immunodeficiency, Centromeric Instability, Facial anomalies). Here we show by our newly generated B-cell-specific Hells conditional knockout mouse model that HELLS plays a pivotal role in T-dependent B-cell responses. HELLS deficiency induces accelerated decay of germinal center (GC) B cells and impairs the generation of high affinity memory B cells and circulating antibodies. Mutant GC B cells undergo dramatic DNA hypomethylation and massive de-repression of evolutionary recent retrotransposons, which surprisingly does not directly affect their survival. Instead, they prematurely upregulate either memory B cell markers or the transcription factor ATF4, which is driving an mTORC1-dependent metabolic program typical of plasma cells. Treatment of wild type mice with a DNMT1-specific inhibitor phenocopies the accelerated kinetics, thus pointing towards DNA-methylation maintenance by HELLS being a crucial mechanism to fine-tune the GC transcriptional program and enable long-lasting humoral immunity.

Date: 2023
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DOI: 10.1038/s41467-023-41317-3

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