An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Genome Research (Impact Factor: 13.85). 09/2010; 20(9):1191-7. DOI: 10.1101/gr.105361.110
Source: PubMed

ABSTRACT Genome-wide association studies (GWAS) routinely identify risk variants in noncoding DNA, as exemplified by reports of multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer in five independent regions in a gene desert on 8q24. Two of these regions also have been associated with breast and colorectal cancer. These findings implicate functional variation within long-range cis-regulatory elements in disease etiology. We used an in vivo bacterial artificial chromosome (BAC) enhancer-trapping strategy in mice to scan a half-megabase of the 8q24 gene desert encompassing the prostate cancer-associated regions for long-range cis-regulatory elements. These BAC assays identified both prostate and mammary gland enhancer activities within the region. We demonstrate that the 8q24 cancer-associated variant rs6983267 lies within an in vivo prostate enhancer whose expression mimics that of the nearby MYC proto-oncogene. Additionally, we show that the cancer risk allele increases prostate enhancer activity in vivo relative to the non-risk allele. This allele-specific enhancer activity is detectable during early prostate development and throughout prostate maturation, raising the possibility that this SNP could assert its influence on prostate cancer risk before tumorigenesis occurs. Our study represents an efficient strategy to build experimentally on GWAS findings with an in vivo method for rapidly scanning large regions of noncoding DNA for functional cis-regulatory sequences harboring variation implicated in complex diseases.

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    • "To date, the majority of identified variants have been found in noncoding regions of the genome (Maurano et al., 2012). Recent evidence suggests that a subset of these variants affect transcriptional mechanisms through modulation of regulatory elements (Musunuru et al., 2010; Pomerantz et al., 2009; Smemo et al., 2012; Tuupanen et al., 2009; van den Boogaard et al., 2012; Visser et al., 2012; Wasserman et al., 2010). Based on the high modularity of regulatory elements, each regulating transcription at different time points and in different tissues, and the high frequency of variants in the population, one can expect that single-nucleotide variants will have only minor contributions to the trait or disease risk. "
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    ABSTRACT: The electrical activity of the heart depends on the correct interplay between key transcription factors and cis-regulatory elements, which together regulate the proper heterogeneous expression of genes encoding for ion channels and other proteins. Genome-wide association studies of ECG parameters implicated genetic variants in the genes for these factors and ion channels modulating conduction and depolarization. Here, we review recent insights into the regulation of localized expression of ion channel genes and the mechanism by which a single-nucleotide polymorphism (SNP) associated with alterations in cardiac conduction patterns in humans affects the transcriptional regulation of the sodium channel genes, SCN5A and SCN10A. The identification of regulatory elements of electrical activity genes helps to explain the impact of genetic variants in non-coding regulatory DNA sequences on regulation of cardiac conduction and the predisposition for cardiac arrhythmias.
    Trends in cardiovascular medicine 12/2013; DOI:10.1016/j.tcm.2013.09.001 · 2.07 Impact Factor
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    • "In some cases, as in the association between prostate cancer and the 8q24 locus, the associated variant has a functional effect (Wasserman et al., 2010). However, for many studies the associated variant has no obvious biologic connection to the disease or trait in question, leading to the notion that the associated variant is in LD with a causal one. "
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    ABSTRACT: BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and environmental factors. Genome-wide association studies have successfully identified five novel loci associated with NSCL/P, including a locus on 1p22.1 near the ABCA4 gene. Because neither expression analysis nor mutation screening support a role for ABCA4 in NSCL/P, we investigated the adjacent gene ARHGAP29. METHODS: Mutation screening for ARHGAP29 protein coding exons was conducted in 180 individuals with NSCL/P and controls from the United States and the Philippines. Nine exons with variants in ARHGAP29 were then screened in an independent set of 872 cases and 802 controls. Arhgap29 expression was evaluated using in situ hybridization in murine embryos. RESULTS: Sequencing of ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Arhgap29 showed craniofacial expression and was reduced in a mouse deficient for Irf6, a gene previously shown to have a critical role in craniofacial development. CONCLUSION: The combination of genome-wide association, rare coding sequence variants, craniofacial specific expression, and interactions with IRF6 support a role for ARHGAP29 in NSCL/P and as the etiologic gene at the 1p22 genome-wide association study locus for NSCL/P. This work suggests a novel pathway in which the IRF6 gene regulatory network interacts with the Rho pathway via ARHGAP29. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 11/2012; 94(11). DOI:10.1002/bdra.23076 · 2.21 Impact Factor
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    • "Indeed, we were able to identify promising candidates that regulate Six1 expression in the PPR (Sato et al., 2010) and the potential regulatory mechanism in the olfactory/ otic/epibranchial placodes (Fig. 5 and see below). Further analysis should enhance our understanding of the etiology of BOR and related syndromes: mutations that affect some of the identified Six1 enhancers might be causative for those disorders as described previously for mutations of SHH (Lettice et al., 2003), RET (Emison et al., 2005) and MYC (Wasserman et al., 2010). "
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    ABSTRACT: The Six1 homeobox gene plays critical roles in vertebrate organogenesis. Mice deficient for Six1 show severe defects in organs such as skeletal muscle, kidney, thymus, sensory organs and ganglia derived from cranial placodes, and mutations in human SIX1 cause branchio-oto-renal syndrome, an autosomal dominant developmental disorder characterized by hearing loss and branchial defects. The present study was designed to identify enhancers responsible for the dynamic expression pattern of Six1 during mouse embryogenesis. The results showed distinct enhancer activities of seven conserved non-coding sequences (CNSs) retained in tetrapod Six1 loci. The activities were detected in all cranial placodes (excluding the lens placode), dorsal root ganglia, somites, nephrogenic cord, notochord and cranial mesoderm. The major Six1-expression domains during development were covered by the sum of activities of these enhancers, together with the previously identified enhancer for the pre-placodal region and foregut endoderm. Thus, the eight CNSs identified in a series of our study represent major evolutionarily conserved enhancers responsible for the expression of Six1 in tetrapods. The results also confirmed that chick electroporation is a robust means to decipher regulatory information stored in vertebrate genomes. Mutational analysis of the most conserved placode-specific enhancer, Six1-21, indicated that the enhancer integrates a variety of inputs from Sox, Pax, Fox, Six, Wnt/Lef1 and basic helix-loop-helix proteins. Positive autoregulation of Six1 is achieved through the regulation of Six protein-binding sites. The identified Six1 enhancers provide valuable tools to understand the mechanism of Six1 regulation and to manipulate gene expression in the developing embryo, particularly in the sensory organs.
    Developmental Biology 05/2012; 368(1):95-108. DOI:10.1016/j.ydbio.2012.05.023 · 3.64 Impact Factor
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