title: PTIP promotes chromatin changes critical for immunoglobulin class switch recombination.
abstract: Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here, we showed that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3)-MLL4 complex display impaired trimethylation of histone 3 at lysine 4 (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus, leading to defective immunoglobulin class switching. We also showed that PTIP accumulation at DSBs contributes to class switch recombination (CSR) and genome stability independently of Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR and suggest a nonredundant role for the MLL3-MLL4 complex in altering antibody effector function.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Margarida Almeida
authors.initials: MA
authors.lastname: Santos
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Wang
authors.forename: Chongzhi
authors.initials: C
authors.lastname: Zang
authors.forename: Kristopher R
authors.initials: KR
authors.lastname: Schwab
authors.forename: Mila
authors.initials: M
authors.lastname: Jankovic
authors.forename: Darius
authors.initials: D
authors.lastname: Filsuf
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.forename: Young-Wook
authors.initials: YW
authors.lastname: Cho
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Dressler
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003564:Cytidine Deaminase / Q000378:metabolism; D004247:DNA; D004268:DNA-Binding Proteins; D006657:Histones / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000502:physiology*; D007134:Immunoglobulin Switch Region; D008745:Methylation; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D015533:Transcriptional Activation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; C412792:Paxip1 protein, mouse; D004247:DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase