B Cell Super-Enhancers and Regulatory Clusters Recruit AID Tumorigenic Activity

被引：204

作者：

Qian, Jason ^{[1
]}

Wang, Qiao ^{[2
]}

Dose, Marei ^{[1
]}

Pruett, Nathanael ^{[1
]}

Kieffer-Kwon, Kyong-Rim ^{[1
]}

Resch, Wolfgang ^{[1
]}

Liang, Genqing ^{[1
]}

Tang, Zhonghui ^{[3
]}

Mathe, Ewy ^{[1
]}

Benner, Christopher ^{[13
]}

Dubois, Wendy ^{[5
]}

Nelson, Steevenson ^{[1
]}

Vian, Laura ^{[1
]}

Oliveira, Thiago Y. ^{[2
]}

Jankovic, Mila ^{[2
]}

Hakim, Ofir ^{[6
]}

Gazumyan, Anna ^{[2
]}

Pavri, Rushad ^{[7
]}

Awasthi, Parirokh ^{[8
]}

Song, Bin ^{[9
]}

Liu, Geng ^{[9
]}

Chen, Longyun ^{[9
]}

Zhu, Shida ^{[9
]}

Feigenbaum, Lionel ^{[8
]}

Staudt, Louis ^{[10
]}

Murre, Cornelis ^{[4
]}

Ruan, Yijun ^{[3
]}

Robbiani, Davide F. ^{[2
]}

Pan-Hammarstrom, Qiang ^{[11
]}

Nussenzweig, Michel C. ^{[2
,12
]}

Casellas, Rafael ^{[1
,5
]}

机构：

[1] NIAMS, NIH, Bethesda, MD 20892 USA

[2] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA

[3] Univ Connecticut, Jackson Lab Genom Med, Dept Genet & Dev Biol, Farmington, CT 06030 USA

[4] Univ Calif San Diego, Div Biol Sci, Dept Mol Biol, La Jolla, CA 92093 USA

[5] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[6] Bar Ilan Univ, IL-5290002 Ramat Gan, Israel

[7] Vienna BioCtr, IMP, A-1030 Vienna, Austria

[8] Sci Applicat Int Corp Frederick, NCI Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA

[9] Beijing Genom Inst, Shenzhen 518083, Peoples R China

[10] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA

[11] Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, S-14186 Stockholm, Sweden

[12] Rockefeller Univ, HHMI, New York, NY 10065 USA

[13] Salk Inst Biol Studies, Integrat Genom & Bioinformat Core, La Jolla, CA 92037 USA

来源：

CELL | 2014年 / 159卷 / 07期

基金：

欧洲研究理事会;

关键词：

INDUCED CYTIDINE DEAMINASE; RNA-POLYMERASE-II; SOMATIC HYPERMUTATION; CHROMOSOMAL TRANSLOCATIONS; MUTATIONAL PROCESSES; GENOMIC INSTABILITY; SEQUENCING REVEALS; DNA; BREAKS; GENE;

D O I：

10.1016/j.cell.2014.11.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1524 / 1537

页数：14

共 57 条

[1] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[2] Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System [J].

Alt, Frederick W. ;

Zhang, Yu ;

Meng, Fei-Long ;

Guo, Chunguang ;

Schwer, Bjoern .

CELL, 2013, 152 (03) :417-429

[3] The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates [J].

Basu, Uttiya ;

Meng, Fei-Long ;

Keim, Celia ;

Grinstein, Veronika ;

Pefanis, Evangelos ;

Eccleston, Jennifer ;

Zhang, Tingting ;

Myers, Darienne ;

Wasserman, Caitlyn R. ;

Wesemann, Duane R. ;

Januszyk, Kurt ;

Gregory, Richard I. ;

Deng, Haiteng ;

Lima, Christopher D. ;

Alt, Frederick W. .

CELL, 2011, 144 (03) :353-363

[4] ELEMENTS REGULATING SOMATIC HYPERMUTATION OF AN IMMUNOGLOBULIN-KAPPA GENE - CRITICAL ROLE FOR THE INTRON ENHANCER MATRIX ATTACHMENT REGION [J].

BETZ, AG ;

MILSTEIN, C ;

GONZALEZFERNANDEZ, A ;

PANNELL, R ;

LARSON, T ;

NEUBERGER, MS .

CELL, 1994, 77 (02) :239-248

[5] Heterogeneity of genomic evolution and mutational profiles in multiple myeloma [J].

Bolli, Niccolo ;

Avet-Loiseau, Herve ;

Wedge, David C. ;

Van Loo, Peter ;

Alexandrov, Ludmil B. ;

Martincorena, Inigo ;

Dawson, Kevin J. ;

Iorio, Francesco ;

Nik-Zainal, Serena ;

Bignell, Graham R. ;

Hinton, Jonathan W. ;

Li, Yilong ;

Tubio, Jose M. C. ;

McLaren, Stuart ;

Meara, Sarah O' ;

Butler, Adam P. ;

Teague, Jon W. ;

Mudie, Laura ;

Anderson, Elizabeth ;

Rashid, Naim ;

Tai, Yu-Tzu ;

Shammas, Masood A. ;

Sperling, Adam S. ;

Fulciniti, Mariateresa ;

Richardson, Paul G. ;

Parmigiani, Giovanni ;

Magrangeas, Florence ;

Minvielle, Stephane ;

Moreau, Philippe ;

Attal, Michel ;

Facon, Thierry ;

Futreal, P. Andrew ;

Anderson, Kenneth C. ;

Campbell, Peter J. ;

Munshi, Nikhil C. .

NATURE COMMUNICATIONS, 2014, 5

[6] Targeting of Somatic Hypermutation by immunoglobulin Enhancer and Enhancer-Like Sequences [J].

Buerstedde, Jean-Marie ;

Alinikula, Jukka ;

Arakawa, Hiroshi ;

McDonald, Jessica J. ;

Schatz, David G. .

PLOS BIOLOGY, 2014, 12 (04)

[7] APOBEC3B is an enzymatic source of mutation in breast cancer [J].

Burns, Michael B. ;

Lackey, Lela ;

Carpenter, Michael A. ;

Rathore, Anurag ;

Land, Allison M. ;

Leonard, Brandon ;

Refsland, Eric W. ;

Kotandeniya, Delshanee ;

Tretyakova, Natalia ;

Nikas, Jason B. ;

Yee, Douglas ;

Temiz, Nuri I. A. ;

Donohue, Duncan E. ;

McDougle, Rebecca M. ;

Brown, William L. ;

Law, Emily K. ;

Harris, Reuben S. .

NATURE, 2013, 494 (7437) :366-370

[8] Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma [J].

Chen, Xiang ;

Bahrami, Armita ;

Pappo, Alberto ;

Easton, John ;

Dalton, James ;

Hedlund, Erin ;

Ellison, David ;

Shurtleff, Sheila ;

Wu, Gang ;

Wei, Lei ;

Parker, Matthew ;

Rusch, Michael ;

Nagahawatte, Panduka ;

Wu, Jianrong ;

Mao, Shenghua ;

Boggs, Kristy ;

Mulder, Heather ;

Yergeau, Donald ;

Lu, Charles ;

Ding, Li ;

Edmonson, Michael ;

Qu, Chunxu ;

Wang, Jianmin ;

Li, Yongjin ;

Navid, Fariba ;

Daw, Najat C. ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Downing, James R. ;

Zhang, Jinghui ;

Dyer, Michael A. .

CELL REPORTS, 2014, 7 (01) :104-112

[9] Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B Cells [J].

Chiarle, Roberto ;

Zhang, Yu ;

Frock, Richard L. ;

Lewis, Susanna M. ;

Molinie, Benoit ;

Ho, Yu-Jui ;

Myers, Darienne R. ;

Choi, Vivian W. ;

Compagno, Mara ;

Malkin, Daniel J. ;

Neuberg, Donna ;

Monti, Stefano ;

Giallourakis, Cosmas C. ;

Gostissa, Monica ;

Alt, Frederick W. .

CELL, 2011, 147 (01) :107-119

[10] Somatic hypermutation in the heavy chain locus correlates with transcription [J].

Fukita, Y ;

Jacobs, H ;

Rajewsky, K .

IMMUNITY, 1998, 9 (01) :105-114

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