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

  • Nat Commun. 2023 Sep 14;14(1):5695. doi: 10.1038/s41467-023-41317-3.
Clara Cousu  #  1 ,  Eléonore Mulot  #  1 ,  Annie De Smet  1 ,  Sara Formichetti  2  3 ,  Damiana Lecoeuche  1 ,  Jianke Ren  4  5 ,  Kathrin Muegge  4 ,  Matthieu Boulard  2 ,  Jean-Claude Weill  1 ,  Claude-Agnès Reynaud  1 ,  Sébastien Storck  6
Affiliations
  • 1. Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades, F-75015, Paris, France.
  • 2. Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), 00015, Monterotondo, Italy.
  • 3. Joint PhD degree program, European Molecular Biology Laboratory and Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 4. Epigenetics Section, Frederick National Laboratory for Cancer Research in the Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
  • 5. NHC Key Lab of Reproduction Regulation,Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200237, China.
  • 6. Université Paris Cité, CNRS UMR 8253, INSERM U1151, Institut Necker Enfants Malades, F-75015, Paris, France. [email protected].
  • # Contributed equally.
PMID: 37709749 DOI: 10.1038/s41467-023-41317-3
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.

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