B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity

Jason Qian; Qiao Wang; Marei Dose; Nathanael Pruett; Kyong Rim Kieffer-Kwon; Wolfgang Resch; Genqing Liang; Zhonghui Tang; Ewy Mathé; Christopher Benner; Wendy Dubois; Steevenson Nelson; Laura Vian; Thiago Y. Oliveira; Mila Jankovic; Ofir Hakim; Anna Gazumyan; Rushad Pavri; Parirokh Awasthi; Bin Song; Geng Liu; Longyun Chen; Shida Zhu; Lionel Feigenbaum; Louis Staudt; Cornelis Murre; Yijun Ruan; Davide F. Robbiani; Qiang Pan-Hammarström; Michel C. Nussenzweig; Rafael Casellas

doi:10.1016/j.cell.2014.11.013

B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity

Jason Qian, Qiao Wang, Marei Dose, Nathanael Pruett, Kyong Rim Kieffer-Kwon, Wolfgang Resch, Genqing Liang, Zhonghui Tang, Ewy Mathé, Christopher Benner, Wendy Dubois, Steevenson Nelson, Laura Vian, Thiago Y. Oliveira, Mila Jankovic, Ofir Hakim, Anna Gazumyan, Rushad Pavri, Parirokh Awasthi, Bin SongGeng Liu, Longyun Chen, Shida Zhu, Lionel Feigenbaum, Louis Staudt, Cornelis Murre, Yijun Ruan, Davide F. Robbiani, Qiang Pan-Hammarström, Michel C. Nussenzweig, Rafael Casellas

Research output: Contribution to journal › Article › peer-review

202 Scopus citations

Abstract

The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA⁺ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.

Original language	English (US)
Pages (from-to)	1524-1537
Number of pages	14
Journal	Cell
Volume	159
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2014.11.013
State	Published - Dec 18 2014
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Qian, J., Wang, Q., Dose, M., Pruett, N., Kieffer-Kwon, K. R., Resch, W., Liang, G., Tang, Z., Mathé, E., Benner, C., Dubois, W., Nelson, S., Vian, L., Oliveira, T. Y., Jankovic, M., Hakim, O., Gazumyan, A., Pavri, R., Awasthi, P., ... Casellas, R. (2014). B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell, 159(7), 1524-1537. https://doi.org/10.1016/j.cell.2014.11.013

Qian, J, Wang, Q, Dose, M, Pruett, N, Kieffer-Kwon, KR, Resch, W, Liang, G, Tang, Z, Mathé, E, Benner, C, Dubois, W, Nelson, S, Vian, L, Oliveira, TY, Jankovic, M, Hakim, O, Gazumyan, A, Pavri, R, Awasthi, P, Song, B, Liu, G, Chen, L, Zhu, S, Feigenbaum, L, Staudt, L, Murre, C, Ruan, Y, Robbiani, DF, Pan-Hammarström, Q, Nussenzweig, MC & Casellas, R 2014, 'B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity', Cell, vol. 159, no. 7, pp. 1524-1537. https://doi.org/10.1016/j.cell.2014.11.013

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title = "B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity",

abstract = "The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.",

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doi = "10.1016/j.cell.2014.11.013",

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AU - Qian, Jason

AU - Wang, Qiao

AU - Dose, Marei

AU - Pruett, Nathanael

AU - Kieffer-Kwon, Kyong Rim

AU - Resch, Wolfgang

AU - Liang, Genqing

AU - Tang, Zhonghui

AU - Mathé, Ewy

AU - Benner, Christopher

AU - Dubois, Wendy

AU - Nelson, Steevenson

AU - Vian, Laura

AU - Oliveira, Thiago Y.

AU - Jankovic, Mila

AU - Hakim, Ofir

AU - Gazumyan, Anna

AU - Pavri, Rushad

AU - Awasthi, Parirokh

AU - Song, Bin

AU - Liu, Geng

AU - Chen, Longyun

AU - Zhu, Shida

AU - Feigenbaum, Lionel

AU - Staudt, Louis

AU - Murre, Cornelis

AU - Ruan, Yijun

AU - Robbiani, Davide F.

AU - Pan-Hammarström, Qiang

AU - Nussenzweig, Michel C.

AU - Casellas, Rafael

PY - 2014/12/18

Y1 - 2014/12/18

N2 - The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.

AB - The antibody gene mutator activation-induced cytidine deaminase (AID) promiscuously damages oncogenes, leading to chromosomal translocations and tumorigenesis. Why nonimmunoglobulin loci are susceptible to AID activity is unknown. Here, we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome but are predominantly grouped within super-enhancers and regulatory clusters. Unexpectedly, in these domains, AID deaminates active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing, we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.

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JF - Cell

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ER -

B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity

Abstract

ASJC Scopus subject areas

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