Pomerantz, M. M., Ahmadiyeh, N., Jia, L., Herman, P., Verzi, M. P., Doddapaneni, H. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882-884

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 07/2009; 41(8):882-4. DOI: 10.1038/ng.403
Source: PubMed


An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that the region harboring this variant is a transcriptional enhancer, that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2) and that the risk region physically interacts with the MYC proto-oncogene. These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant.

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Available from: Matthew J Davis, Apr 17, 2014
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    • "It was shown that this disease could originate from mutations in a lamin protein that specifically causes abnormal retention and silencing of muscle-specific genes at the nuclear envelope [17]. The importance of spatial genome organization in human disease is equally well demonstrated in cancers where single nucleotide polymorphisms (SNPs) were found to create novel enhancers acting long-range to activate distal genes through DNA looping [18-20]. "
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    ABSTRACT: Background Although genetic or epigenetic alterations have been shown to affect the three-dimensional organization of genomes, the utility of chromatin conformation in the classification of human disease has never been addressed. Results Here, we explore whether chromatin conformation can be used to classify human leukemia. We map the conformation of the HOXA gene cluster in a panel of cell lines with 5C chromosome conformation capture technology, and use the data to train and test a support vector machine classifier named 3D-SP. We show that 3D-SP is able to accurately distinguish leukemias expressing MLL-fusion proteins from those expressing only wild-type MLL, and that it can also classify leukemia subtypes according to MLL fusion partner, based solely on 5C data. Conclusions Our study provides the first proof-of-principle demonstration that chromatin conformation contains the information value necessary for classification of leukemia subtypes.
    Genome Biology 04/2014; 15(4):R60. DOI:10.1186/gb-2014-15-4-r60 · 10.81 Impact Factor
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    • "In colorectal cancer (CRC), one well-characterized loop is between a locus 335 kb upstream of MYC (MYC-335) and the MYC promoter. MYC-335, the site harboring an important CRC risk SNP (rs6983267), is a transcriptional enhancer that promotes the binding of transcription factor 4 (TCF4) specifically in CRC22,23. Importantly, mice lacking MYC-335 were resistant to intestinal tumors, although MYC transcripts were only modestly reduced24. Very recently, the region upstream of MYC has been reported to contain an exceptionally large super-enhancer17 and such a super-enhancer is tumor type specific in cancer cells, but not in its healthy counterparts20. "
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    ABSTRACT: The human 8q24 gene desert contains multiple enhancers that form tissue-specific long-range chromatin loops with the MYC oncogene, but how chromatin looping at the MYC locus is regulated remains poorly understood. Here we demonstrate that a long noncoding RNA (lncRNA), CCAT1-L, is transcribed specifically in human colorectal cancers from a locus 515 kb upstream of MYC. This lncRNA plays a role in MYC transcriptional regulation and promotes long-range chromatin looping. Importantly, the CCAT1-L locus is located within a strong super-enhancer and is spatially close to MYC. Knockdown of CCAT1-L reduced long-range interactions between the MYC promoter and its enhancers. In addition, CCAT1-L interacts with CTCF and modulates chromatin conformation at these loop regions. These results reveal an important role of a previously unannotated lncRNA in gene regulation at the MYC locus.Cell Research advance online publication 25 March 2014; doi:10.1038/cr.2014.35.
    Cell Research 03/2014; 24(9). DOI:10.1038/cr.2014.35 · 12.41 Impact Factor
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    • "Enhancers, which are key to the precise regulation of spatiotemporal gene expression, often reside at a distance from their target genes (Maston et al. 2006) and function through long-range regulatory mechanisms (Glinskii et al. 2011; Lettice et al. 2003; Pomerantz et al. 2009). Although some enhancers are found in the proximity of the transcription start sites of their target gene, there is mounting evidence of distant enhancers incorporated into the structure of neighboring genes or looping over intermediate unaffected genes (Irimia et al. 2012; Lettice et al. 2003; Perry et al. 2010; Visser et al. 2012). "
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    ABSTRACT: We investigated discriminating features between enhancers separated from their target genes by at least one intermediate gene/exon (named tele-enhancers in this study) and enhancers residing inside the target gene locus. In this study, we used genome-scale enhancer maps and whole-genome gene expression profiles to establish a large panel of heart tele-enhancers. By contrasting tele-enhancers to proximal heart enhancers located in the neighborhood of heart genes, we observed that heart tele-enhancers employ unique regulatory mechanisms based on cardiac transcription factor SRF, TEAD, and NKX-2.5, while proximal heart enhancers rely on GATA4 factors. A functional analysis shows that tele-enhancers preferentially regulate house-keeping genes and play a metabolic role during heart development. In addition, with 1) lower nucleotide divergence, 2) lower single-nucleotide polymorphism (SNP) density, and 3) smaller proportion of low derived-allele-frequency SNPs, tele-enhancers are significantly more conserved than their proximal counterparts. Similar trends have been observed in non-heart tissues and cell types, suggesting that our findings are general characteristics of tele-enhancers.
    G3-Genes Genomes Genetics 02/2014; 4(4). DOI:10.1534/g3.114.010447 · 3.20 Impact Factor
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