CTCF is a highly conserved 11 Zn finger (ZF) transcription factor and insulator protein. CTCF is involved in multiple aspects of gene regulation including promoter activation and repression, hormone-responsive gene silencing, methylation-dependent chromatin insulation, and genomic imprinting. Moreover, our recent discovery of a methylationsensitive CTCF insulator at the DM1 locus that might be responsible for the severe phenotype of Congenital Myotonic Dystrophy (Filippova et al.,2001), and our preliminary data on the role of CTCF insulators in X chromosome inactivation strongly suggest a link between CTCF and epigenetic regulation in development. Several findings also point to a role for CTCF as a tumor suppressor gene in both cancer epigenetics and genetics. Aberrant methylation of certain CTCF target sites, that is predicted to prevent CTCF-binding, has been demonstrated in a number of tumors. CTCF maps to human chromosome 16q22, within a region that displays frequent cancer-associated deletions (Filippova et al.,1998). We have observed somatic missense mutations within the CTCF 11ZF DNA-binding domain in breast, prostate and Wilms' tumors (Filippova et al.,2002). CTCF +/- mice exhibit enhanced tumor development in multiple tissues. Homozygous deletion of the CTCF results in early embryonic lethality, whereas the CTCF heterozygous mice exhibit decreased embryonic survival. Our broad and longterm hypothesis is that certain functions of CTCF are essential in early development and maintaining cell viability, whereas its other functions, when lost, result in the malignant phenotype. To test this hypothesis our specific aims will: Extend our studies on the role of CTCF in tumorigenesis (Aim 1) and early embryonic development (Aim 2). We will determine what genetic and epigenetic mechanisms are involved in CTCF haploinsufficiency. And finally (Aim 3), we will use the Cre-loxP system to generate a conditional CTCF mutant allele, that in combination with various tissue-specific Cre transgenic mice will allow us to test the hypothesis that complete loss of CTCF function leads to cell death in both normal and/or malignant cells, whereas loss of one CTCF allele in somatic tissue predisposes to tumor development. We will also generate knock-in mice harboring CTCF Zn finger point mutations that we have observed in human tumors to determine the functional significance of such mutated alleles in tumor predisposition. The significance of this proposal is that identifying the mechanisms of the CTCF haploinsufficiency will provide new insight into the broad spectrum of clinical human cancer phenotypes associated with LOH at 16q22.1 where CTCF maps. The health-relatedness is that the identified mechanisms can be targeted for both cancer prevention and therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Mietz, Judy
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Fred Hutchinson Cancer Research Center
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Kemp, Christopher J; Moore, James M; Moser, Russell et al. (2014) CTCF haploinsufficiency destabilizes DNA methylation and predisposes to cancer. Cell Rep 7:1020-9
Moore, James M; Rabaia, Natalia A; Smith, Leslie E et al. (2012) Loss of maternal CTCF is associated with peri-implantation lethality of Ctcf null embryos. PLoS One 7:e34915
Libby, Randell T; Hagerman, Katharine A; Pineda, Victor V et al. (2008) CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet 4:e1000257
Filippova, Galina N (2008) Genetics and epigenetics of the multifunctional protein CTCF. Curr Top Dev Biol 80:337-60
Ladd, Paula D; Smith, Leslie E; Rabaia, Natalia A et al. (2007) An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 16:3174-87
Filippova, Galina N; Cheng, Mimi K; Moore, James M et al. (2005) Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev Cell 8:31-42
Kemp, Christopher J (2005) Multistep skin cancer in mice as a model to study the evolution of cancer cells. Semin Cancer Biol 15:460-73
Disteche, C M; Filippova, G N; Tsuchiya, K D (2002) Escape from X inactivation. Cytogenet Genome Res 99:36-43
Filippova, Galina N; Qi, Chen-Feng; Ulmer, Jonathan E et al. (2002) Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity. Cancer Res 62:48-52
Filippova, G N; Thienes, C P; Penn, B H et al. (2001) CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus. Nat Genet 28:335-43

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