Germinal center output is sustained by HELLS-dependent DNA methylation maintenance in B cells
COUSU C. 1, MULOT E. 1, DE SMET A. 1, FORMICHETTI S. 2, LECOEUCHE D. 1, REN J. 3, MUEGGE K. 3, BOULARD M. 2, REYNAUD C. 1, WEILL J. 1, STORCK S. 1
1 Université Paris Cité, CNRS, INSERM U1151, Institut Necker Enfants Malades, Paris, France; 2 Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy; 3 Epigenetics Section, Frederick National Laboratory for Cancer Research in the Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Md 21702, United States
HELLS/LSH (Helicase, Lymphoid Specific) is a SNF2-like chromatin remodeler involved in DNA methylation. Its loss-of-function in humans causes a humoral immunodeficiency, the ICF4 syndrome (Immunodeficiency, Centromeric Instability and Facial anomalies). We generated B-cell-specific Hells conditional knockout mice to elucidate its functions during T-dependent B cell responses. Hells deficiency induces an 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 derepression of evolutionary recent retrotransposons, which surprisingly does not affect their survival. Instead, they prematurely upregulate either memory B cell markers or the ATF4 transcription factor with a so far unappreciated role in driving an mTORC1-dependent metabolic program typical of plasma cells. Since treatment with a DNMT1-specific inhibitor phenocopies the accelerated kinetics, these results identify DNA-methylation maintenance by HELLS as a crucial mechanism to finely tune the GC transcriptional program and enable long-lived humoral immunity.