title: De novo DNA Methyltransferases Dnmt3a and Dnmt3b regulate the onset of Igκ light chain rearrangement during early B-cell development.
abstract: Immunoglobulin genes V(D)J rearrangement during early lymphopoiesis is a critical process involving sequential recombination of the heavy and light chain loci. A number of transcription factors act together with temporally activated recombinases and chromatin accessibility changes to regulate this complex process. Here, we deleted the de novo DNA methyltransferases Dnmt3a and Dnmt3b in early B cells of conditionally targeted mice, and monitored the process of V(D)J recombination. Dnmt3a and Dnmt3b deletion resulted in precocious recombination of the immunoglobulin κ light chain without impairing the differentiation of mature B cells or overall B-cell development. Ex vivo culture of IL-7 restricted early B-cell progenitors lacking Dnmt3a and Dnmt3b showed precocious Vκ-Jκ rearrangements that are limited to the proximal Vκ genes. Furthermore, B-cell progenitors deficient in Dnmt3a and Dnmt3b showed elevated levels of germline transcripts at the proximal Vκ genes, alterations in methylation patterns at Igκ enhancer sites and increased expression of the transcription factor E2A. Our data suggest that Dnmt3a and Dnmt3b are critical to regulate the onset of Igκ light chain rearrangement during early B-cell development.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Anand
authors.initials: A
authors.lastname: Manoharan
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Du Roure
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Antonius G
authors.initials: AG
authors.lastname: Rolink
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.|Faculty of Sciences, University of Basel, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology*; D000090205:DNA Methyltransferase 3A; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology; D060152:V(D)J Recombination / Q000276:immunology*; D000097584:DNA Methyltransferase 3B
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D007145:Immunoglobulin kappa-Chains; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C075668:Tcf3 protein, mouse
keywords: B-cell; DNA methylation; Immunoglobulin; V(D)J rearrangement