PTIP promotes chromatin changes critical for immunoglobulin class switch recombination.
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.
Daniel
Jeremy A
JA
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Santos
Margarida Almeida
MA
Wang
Zhibin
Z
Zang
Chongzhi
C
Schwab
Kristopher R
KR
Jankovic
Mila
M
Filsuf
Darius
D
Chen
Hua-Tang
HT
Gazumyan
Anna
A
Yamane
Arito
A
Cho
Young-Wook
YW
Sun
Hong-Wei
HW
Ge
Kai
K
Peng
Weiqun
W
Nussenzweig
Michel C
MC
Casellas
Rafael
R
Dressler
Gregory R
GR
Zhao
Keji
K
Nussenzweig
André
A
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)
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