title: The histone chaperone Spt6 is required for activation-induced cytidine deaminase target determination through H3K4me3 regulation.
abstract: H3K4me3 plays a critical role in the activation-induced cytidine deaminase (AID)-induced DNA cleavage of switch (S) regions in the immunoglobulin heavy chain (IgH) locus during class-switch recombination (CSR). The histone chaperone complex facilitates chromatin transcription (FACT) is responsible for forming H3K4me3 at AID target loci. Here we show that the histone chaperone suppressor of Ty6 (Spt6) also participates in regulating H3K4me3 for CSR and for somatic hypermutation in AID target loci. We found that H3K4me3 loss was correlated with defects in AID-induced DNA breakage and reduced mutation frequencies in IgH loci in both S and variable regions and in non-IgH loci such as metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and small nucleolar RNA host gene 3 (SNHG3). Global gene expression analysis revealed that Spt6 can act as both a positive and negative transcriptional regulator in B cells, affecting ∼5% of the genes that includes suppressor of Ty4 (Spt4) and AID. Interestingly, Spt6 regulates CSR and AID expression through two distinct histone modification pathways, H3K4me3 and H3K36me3, respectively. Tandem SH2 domain of Spt6 plays a critical role in CSR and H3K4me3 regulation involving Set1 histone methyltransferase. We conclude that Spt6 is a unique histone chaperone capable of regulating the histone epigenetic state of both AID targets and the AID locus.
authors: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Sakyo-ku, Kyoto 606-8501, Japan. nasim@mfour.med.kyoto-u.ac.jp
authors: Nasim A
authors: NA
authors: Begum
authors: Andre
authors: A
authors: Stanlie
authors: Mikiyo
authors: M
authors: Nakata
authors: Hideo
authors: H
authors: Akiyama
authors: Tasuku
authors: T
authors: Honjo
mesh_terms: D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D053960:DNA Breaks; D044127:Epigenesis, Genetic / Q000502:physiology*; D056426:Genetic Loci / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000502:physiology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D006657:Histones; D007143:Immunoglobulin Heavy Chains; C557041:MALAT1 long non-coding RNA, human; D018832:Molecular Chaperones; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; C481011:SUPT4H1 protein, human; C100927:SUPT6H protein, human; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; C526068:Setd1A protein, human; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase