PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

Jeremy A. Daniel; Margarida Almeida Santos; Zhibin Wang; Chongzhi Zang; Kristopher R. Schwab; Mila Jankovic; Darius Filsuf; Hua Tang Chen; Anna Gazumyan; Arito Yamane; Young Wook Cho; Hong Wei Sun; Kai Ge; Weiqun Peng; Michel C. Nussenzweig; Rafael Casellas; Gregory R. Dressler; Keji Zhao; André Nussenzweig

doi:10.1126/science.1187942

PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

Jeremy A. Daniel, Margarida Almeida Santos, Zhibin Wang, Chongzhi Zang, Kristopher R. Schwab, Mila Jankovic, Darius Filsuf, Hua Tang Chen, Anna Gazumyan, Arito Yamane, Young Wook Cho, Hong Wei Sun, Kai Ge, Weiqun Peng, Michel C. Nussenzweig, Rafael Casellas, Gregory R. Dressler, Keji Zhao, André Nussenzweig

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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.

Original language	English (US)
Pages (from-to)	917-923
Number of pages	7
Journal	Science
Volume	329
Issue number	5994
DOIs	https://doi.org/10.1126/science.1187942
State	Published - Aug 20 2010
Externally published	Yes

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Daniel, J. A., Santos, M. A., Wang, Z., Zang, C., Schwab, K. R., Jankovic, M., Filsuf, D., Chen, H. T., Gazumyan, A., Yamane, A., Cho, Y. W., Sun, H. W., Ge, K., Peng, W., Nussenzweig, M. C., Casellas, R., Dressler, G. R., Zhao, K., & Nussenzweig, A. (2010). PTIP promotes chromatin changes critical for immunoglobulin class switch recombination. Science, 329(5994), 917-923. https://doi.org/10.1126/science.1187942

Daniel, JA, Santos, MA, Wang, Z, Zang, C, Schwab, KR, Jankovic, M, Filsuf, D, Chen, HT, Gazumyan, A, Yamane, A, Cho, YW, Sun, HW, Ge, K, Peng, W, Nussenzweig, MC, Casellas, R, Dressler, GR, Zhao, K & Nussenzweig, A 2010, 'PTIP promotes chromatin changes critical for immunoglobulin class switch recombination', Science, vol. 329, no. 5994, pp. 917-923. https://doi.org/10.1126/science.1187942

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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.",

author = "Daniel, {Jeremy A.} and Santos, {Margarida Almeida} and Zhibin Wang and Chongzhi Zang and Schwab, {Kristopher R.} and Mila Jankovic and Darius Filsuf and Chen, {Hua Tang} and Anna Gazumyan and Arito Yamane and Cho, {Young Wook} and Sun, {Hong Wei} and Kai Ge and Weiqun Peng and Nussenzweig, {Michel C.} and Rafael Casellas and Dressler, {Gregory R.} and Keji Zhao and Andr{\'e} Nussenzweig",

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doi = "10.1126/science.1187942",

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AU - Daniel, Jeremy A.

AU - Santos, Margarida Almeida

AU - Wang, Zhibin

AU - Zang, Chongzhi

AU - Schwab, Kristopher R.

AU - Jankovic, Mila

AU - Filsuf, Darius

AU - Chen, Hua Tang

AU - Gazumyan, Anna

AU - Yamane, Arito

AU - Cho, Young Wook

AU - Sun, Hong Wei

AU - Ge, Kai

AU - Peng, Weiqun

AU - Nussenzweig, Michel C.

AU - Casellas, Rafael

AU - Dressler, Gregory R.

AU - Zhao, Keji

AU - Nussenzweig, André

PY - 2010/8/20

Y1 - 2010/8/20

N2 - 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.

AB - 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.

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PTIP promotes chromatin changes critical for immunoglobulin class switch recombination

Abstract

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