CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer

被引：145

作者：

Kemp, Christopher J. ^{[1
]}

Moore, James M. ^{[1
]}

Moser, Russell ^{[1
]}

Bernard, Brady ^{[2
]}

Teater, Matt ^{[3
]}

Smith, Leslie E. ^{[1
]}

Rabaia, Natalia A. ^{[1
]}

Gurley, Kay E. ^{[1
]}

Guinney, Justin ^{[4
]}

Busch, Stephanie E. ^{[1
]}

Shaknovich, Rita ^{[3
]}

Lobanenkov, Victor V. ^{[5
]}

Liggitt, Denny ^{[6
]}

Shmulevich, Ilya ^{[2
]}

Melnick, Ari ^{[3
]}

Filippova, Galina N. ^{[1
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA

[2] Inst Syst Biol, Seattle, WA 98106 USA

[3] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY 10021 USA

[4] Sage Bionetworks, Seattle, WA 98109 USA

[5] NIAID, Mol Pathol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA

[6] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA

来源：

CELL REPORTS | 2014年 / 7卷 / 04期

关键词：

PROTEIN CTCF; TRANSCRIPTION FACTOR; BINDING-SITES; GENOME-WIDE; BREAST; SPECIFICITY; MUTATIONS; GENETICS; GENES; MAP;

D O I：

10.1016/j.celrep.2014.04.004

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Epigenetic alterations, particularly in DNA methylation, are ubiquitous in cancer, yet the molecular origins and the consequences of these alterations are poorly understood. CTCF, a DNA-binding protein that regulates higher-order chromatin organization, is frequently altered by hemizygous deletion or mutation in human cancer. To date, a causal role for CTCF in cancer has not been established. Here, we show that Ctcf hemizygous knockout mice are markedly susceptible to spontaneous, radiation-, and chemically induced cancer in a broad range of tissues. Ctcf(+/-) tumors are characterized by increased aggressiveness, including invasion, metastatic dissemination, and mixed epithelial/mesenchymal differentiation. Molecular analysis of Ctcf(+/-) tumors indicates that Ctcf is haploinsufficient for tumor suppression. Tissues with hemizygous loss of CTCF exhibit increased variability in CpG methylation genome wide. These findings establish CTCF as a prominent tumor-suppressor gene and point to CTCF-mediated epigenetic stability as a major barrier to neoplastic progression.

引用

页码：1020 / 1029

页数：10

共 25 条

[1] Base-Pair Resolution DNA Methylation Sequencing Reveals Profoundly Divergent Epigenetic Landscapes in Acute Myeloid Leukemia [J].

Akalin, Altuna ;

Garrett-Bakelman, Francine E. ;

Kormaksson, Matthias ;

Busuttil, Jennifer ;

Zhang, Lu ;

Khrebtukova, Irina ;

Milne, Thomas A. ;

Huang, Yongsheng ;

Biswas, Debabrata ;

Hess, Jay L. ;

Allis, C. David ;

Roeder, Robert G. ;

Valk, Peter J. M. ;

Lowenberg, Bob ;

Delwel, Ruud ;

Fernandez, Hugo F. ;

Paietta, Elisabeth ;

Tallman, Martin S. ;

Schroth, Gary P. ;

Mason, Christopher E. ;

Melnick, Ari ;

Figueroa, Maria E. .

PLOS GENETICS, 2012, 8 (06)

[2] Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene [J].

Bell, AC ;

Felsenfeld, G .

NATURE, 2000, 405 (6785) :482-485

[3]

Berx G, 1996, ONCOGENE, V13, P1919

[4] Aberration in DNA Methylation in B-Cell Lymphomas Has a Complex Origin and Increases with Disease Severity [J].

De, Subhajyoti ;

Shaknovich, Rita ;

Riester, Markus ;

Elemento, Olivier ;

Geng, Huimin ;

Kormaksson, Matthias ;

Jiang, Yanwen ;

Woolcock, Bruce ;

Johnson, Nathalie ;

Polo, Jose M. ;

Cerchietti, Leandro ;

Gascoyne, Randy D. ;

Melnick, Ari ;

Michor, Franziska .

PLOS GENETICS, 2013, 9 (01)

[5] Genetics and epigenetics of the multifunctional protein CTCF [J].

Filippova, Galina N. .

CURRENT TOPICS IN DEVELOPMENTAL BIOLOGY, VOL 80, 2008, 80 :337-360

[6]

Filippova GN, 2002, CANCER RES, V62, P48

[7]

Filippova GN, 1998, GENE CHROMOSOME CANC, V22, P26, DOI 10.1002/(SICI)1098-2264(199805)22:1<26::AID-GCC4>3.3.CO

[8]

2-W

[9] Integrated genomic characterization of endometrial carcinoma [J].

Getz, Gad ;

Gabriel, Stacey B. ;

Cibulskis, Kristian ;

Lander, Eric ;

Sivachenko, Andrey ;

Sougnez, Carrie ;

Lawrence, Mike ;

Kandoth, Cyriac ;

Dooling, David ;

Fulton, Robert ;

Fulton, Lucinda ;

Kalicki-Veizer, Joelle ;

McLellan, Michael D. ;

O'Laughlin, Michelle ;

Schmidt, Heather ;

Wilson, Richard K. ;

Ye, Kai ;

Ding, Li ;

Mardis, Elaine R. ;

Ally, Adrian ;

Balasundaram, Miruna ;

Birol, Inanc ;

Butterfield, Yaron S. N. ;

Carlsen, Rebecca ;

Carter, Candace ;

Chu, Andy ;

Chuah, Eric ;

Chun, Hye-Jung E. ;

Dhalla, Noreen ;

Guin, Ranabir ;

Hirst, Carrie ;

Holt, Robert A. ;

Jones, Steven J. M. ;

Lee, Darlene ;

Li, Haiyan I. ;

Marra, Marco A. ;

Mayo, Michael ;

Moore, Richard A. ;

Mungall, Andrew J. ;

Plettner, Patrick ;

Schein, Jacqueline E. ;

Sipahimalani, Payal ;

Tam, Angela ;

Varhol, Richard J. ;

Robertson, A. Gordon ;

Pashtan, Itai ;

Saksena, Gordon ;

Onofrio, Robert C. ;

Schumacher, Steven E. ;

Tabak, Barbara .

NATURE, 2013, 497 (7447) :67-73

[10]

Gurley K.E., 2014, MOUSE MODELS CANC, P63

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