title: GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy.
abstract: Somatic hypermutation in B cells is initiated by activation-induced cytidine deaminase-catalyzed C→U deamination at immunoglobulin variable regions. Here we investigate the role of the germinal centre-associated nuclear protein (GANP) in enhancing the access of activation-induced cytidine deaminase (AID) to immunoglobulin variable regions. We show that the nuclear export factor GANP is involved in chromatin modification at rearranged immunoglobulin variable loci, and its activity requires a histone acetyltransferase domain. GANP interacts with the transcription stalling protein Spt5 and facilitates RNA Pol-II recruitment to immunoglobulin variable regions. Germinal centre B cells from ganp-transgenic mice showed a higher AID occupancy at the immunoglobulin variable region, whereas B cells from conditional ganp-knockout mice exhibit a lower AID accessibility. These findings suggest that GANP-mediated chromatin modification promotes transcription complex recruitment and positioning at immunoglobulin variable loci to favour AID targeting.
authors: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors: Shailendra Kumar
authors: SK
authors: Singh
authors: Kazuhiko
authors: K
authors: Maeda
authors: Mohammed Mansour Abbas
authors: MM
authors: Eid
authors: Sarah Ameen
authors: SA
authors: Almofty
authors: Masaya
authors: M
authors: Ono
authors: Phuong
authors: P
authors: Pham
authors: Myron F
authors: MF
authors: Goodman
authors: Nobuo
authors: N
authors: Sakaguchi
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000235:genetics; D018858:Germinal Center / Q000166:cytology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C481510:GANP protein, mouse; D006657:Histones; D007135:Immunoglobulin Variable Region; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D009707:Nucleosomes; D010750:Phosphoproteins; D004247:DNA; D000123:Acetyltransferases; C406825:MCM3AP protein, human; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
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