title: Localized DNA demethylation at recombination intermediates during immunoglobulin heavy chain gene assembly.
abstract: Multiple epigenetic marks have been proposed to contribute to the regulation of antigen receptor gene assembly via V(D)J recombination. Here we provide a comprehensive view of DNA methylation at the immunoglobulin heavy chain (IgH) gene locus prior to and during V(D)J recombination. DNA methylation did not correlate with the histone modification state on unrearranged alleles, indicating that these epigenetic marks were regulated independently. Instead, pockets of tissue-specific demethylation were restricted to DNase I hypersensitive sites within this locus. Though unrearranged diversity (D(H)) and joining (J(H)) gene segments were methylated, DJ(H) junctions created after the first recombination step were largely demethylated in pro-, pre-, and mature B cells. Junctional demethylation was highly localized, B-lineage-specific, and required an intact tissue-specific enhancer, Eμ. We propose that demethylation occurs after the first recombination step and may mark the junction for secondary recombination.
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors: Roza
authors: R
authors: Selimyan
authors: Rachel M
authors: RM
authors: Gerstein
authors: Irina
authors: I
authors: Ivanova
authors: Patricia
authors: P
authors: Precht
authors: Ramesh
authors: R
authors: Subrahmanyam
authors: Thomas
authors: T
authors: Perlot
authors: Frederick W
authors: FW
authors: Alt
authors: Ranjan
authors: R
authors: Sen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D003850:Deoxyribonuclease I; D004742:Enhancer Elements, Genetic; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D050438:Genes, Immunoglobulin Heavy Chain; D006657:Histones / Q000235:genetics / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012045:Regulatory Sequences, Nucleic Acid; D013601:T-Lymphocytes / Q000276:immunology; D060152:V(D)J Recombination
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C499308:Rag2 protein, mouse; D003850:Deoxyribonuclease I
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