title: Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination.
abstract: Immunoglobulin class switch recombination (CSR) is initiated by double-stranded DNA breaks (DSBs) in switch regions triggered by activation-induced cytidine deaminase (AID). Although CSR correlates with epigenetic modifications at the IgH locus, the relationship between these modifications and AID remains unknown. In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain-associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (Sμ) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to Sμ, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR.
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de Santé et de Recherche Médicale Unité 964/Centre National de Recherche Scientifique Unité Mixte de Recherche 7104, Université de Strasbourg, 67404 Illkirch, France.
authors: Beena Patricia
authors: BP
authors: Jeevan-Raj
authors: Isabelle
authors: I
authors: Robert
authors: Vincent
authors: V
authors: Heyer
authors: Adeline
authors: A
authors: Page
authors: Jing H
authors: JH
authors: Wang
authors: Florence
authors: F
authors: Cammas
authors: Frederick W
authors: FW
authors: Alt
authors: Régine
authors: R
authors: Losson
authors: Bernardo
authors: B
authors: Reina-San-Martin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D002850:Chromatography, Gel; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003564:Cytidine Deaminase / Q000276:immunology*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic / Q000276:immunology*; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007134:Immunoglobulin Switch Region / Q000276:immunology*; D017404:In Situ Hybridization, Fluorescence; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000076183:Tripartite Motif-Containing Protein 28; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase