Mice Lacking a
            <i>Myc</i>
            Enhancer That Includes Human SNP rs6983267 Are Resistant to Intestinal Tumors

Sur, Inderpreet; Hallikas, Outi; Vähärautio, Anna; Yan, Jian; Turunen, Mikko; Enge, Martin; Taipale, Minna; Karhu, Auli; Aaltonen, Lauri A.; Taipale, Jussi

doi:10.1126/science.1228606

Cited by 199 publications

(200 citation statements)

References 32 publications

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“…Additionally, we demonstrate that three of three SNPs previously shown to alter long-range enhancer function [rs12740374/ SORT1 (18) and rs6983267/MYC (19,20)] or to reside in a longrange contact point [rs7578326/IRS1 (21)] overlap a stretch enhancer specifically in the relevant cell type(s) (SI Appendix, Fig. S7 I-K).…”

Section: Significancementioning

confidence: 74%

Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants

Parker

Stitzel

Taylor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

637

672

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Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (≥3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases.

show abstract

Section: Significancementioning

confidence: 74%

Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants

Parker

Stitzel

Taylor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

637

672

View full text Add to dashboard Cite

show abstract

“…On the other hand, a recent mouse model underscores the importance of the rs6983267 enhancer region in colon cancer (Sur et al 2012). Deletion of the enhancer in the mouse germ line had a minor effect on MYC expression but no effect on development, consistent with the lack of eQTL influence in humans.…”

Section: Myc Expression and Cancer Riskmentioning

confidence: 75%

“…Deletion of the enhancer in the mouse germ line had a minor effect on MYC expression but no effect on development, consistent with the lack of eQTL influence in humans. In contrast, crossing the rs6983267 enhancer-deficient line to the "APCmin" mouse, which harbors a germ line mutation in the APC tumor suppressor, leads to a dramatic reduction in intestinal tumor development (Sur et al 2012). These observations provide a graphic demonstration of the essential role of the rs6983267 enhancer as a "target" of the excessive Wnt signaling found in colon cancers.…”

Section: Myc Expression and Cancer Riskmentioning

confidence: 99%

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Cole

2014

Cold Spring Harbor Perspectives in Medicine

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MYC is one of the most frequently mutated and overexpressed genes in human cancer but the regulation of MYC expression and the ability of MYC protein to repress cellular genes (including itself ) have remained mysterious. Recent genome-wide association studies show that many genetic polymorphisms associated with disease risk map to distal regulatory elements that regulate the MYC promoter through large chromatin loops. Cancer risk-associated single-nucleotide polymorphisms (SNPs) contain more potent enhancer activity, promoting higher MYC levels and a greater risk of disease. The MYC promoter is also subject to complex regulatory circuits and limits its own expression by a feedback loop. A model for MYC autoregulation is discussed which involves a signaling pathway between the PTEN ( phosphatase and tensin homolog) tumor suppressor and repressive histone modifications laid down by the EZH2 methyltransferase.

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“…28,29 Indeed, this connection intensified following reports that the 8q24 locus revealed by GWAS of a number of cancers, including colorectal carcinomas, was due to an extreme upstream TCF7L2-binding element driving the transcription of MYC. [30][31][32] In addition, it has been shown that when TCF7L2 recurrently fuses with its neighboring gene, VTI1A, colorectal adenocarcinomas result. Curiously, many of the other GWASimplicated loci associated with T2D are also associated with the risk for prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2

et al. 2014

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Resolving the underlying functional mechanism to a given genetic association has proven extremely challenging. However, the strongest associated type 2 diabetes (T2D) locus reported to date, TCF7L2, presents an opportunity for translational analyses, as many studies in multiple ethnicities strongly point to SNP rs7903146 in intron 3 as being the causal variant within this gene. We carried out oligo pull-down combined with mass spectrophotometry (MS) to elucidate the specific transcriptional machinery across this SNP using protein extracts from HCT116 cells. We observed that poly (ADP-ribose) polymerase 1 (PARP-1) is by far the most abundant binding factor. Pursuing the possibility of a feedback mechanism, we observed that PARP-1, along with the next most abundant binding proteins, DNA topoisomerase I and ATP-dependent RNA helicase A, dimerize with the TCF7L2 protein and with each other. We uncovered further evidence of a feedback mechanism using a luciferase reporter approach, including observing expression differences between alleles for rs7903146. We also found that there was an allelic difference in the MS results for proteins with less abundant binding, namely X-ray repair cross-complementing 5 and RPA/p70. Our results point to a protein complex binding across rs7903146 within TCF7L2 and suggests a possible mechanism by which this locus confers its T2D risk.

show abstract

Mice Lacking a Myc Enhancer That Includes Human SNP rs6983267 Are Resistant to Intestinal Tumors

Cited by 199 publications

References 32 publications

Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants

Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2

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