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Functional enhancers at the gene-poor 8q24 cancer-linked locus.

Jia L, Landan G, Pomerantz M, Jaschek R, Herman P, Reich D, Yan C, Khalid O, Kantoff P, Oh W, Manak JR, Berman BP, Henderson BE, Frenkel B, Haiman CA, Freedman M, Tanay A, Coetzee GA - PLoS Genet. (2009)

Bottom Line: Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR).Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness.The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

View Article: PubMed Central - PubMed

Affiliation: USC/Norris Cancer Center, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.

ABSTRACT
Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

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Enhancer-chromatin patterns on the risk regions.Epigenomic patterns at the risk intervals. Shown are the epigenomic profiles we derived for the 8q24 risk intervals. Specific regions enriched with AcH3 and AROR occupancy were isolated for further analysis (black marks labeled AcP1 to AcP15). Risk regions 1 and 3 are shown in higher resolution in the inset.
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pgen-1000597-g003: Enhancer-chromatin patterns on the risk regions.Epigenomic patterns at the risk intervals. Shown are the epigenomic profiles we derived for the 8q24 risk intervals. Specific regions enriched with AcH3 and AROR occupancy were isolated for further analysis (black marks labeled AcP1 to AcP15). Risk regions 1 and 3 are shown in higher resolution in the inset.

Mentions: A higher-resolution epigenetic map of the risk regions in LNCaP is shown in Figure 3. As noted above, regions 1 and 3 were not robustly transcribed in either the normal tissues or prostate cancer cell lines. The histones in this region, however, were highly modified in LNCaP, with particular enrichment for active chromatin marks, i.e. AcH3, H3K4me1 and H3K4me3. Additionally we observed significant occupancy of AR and RNAPII. Importantly, these patterns of activity were absent from PC3, which does not express the AR. The risk regions were also enriched for the elongation mark H3K36me3; however, in line with the general lack of transcription, the H3K36me3 areas were not polarized to a specific side of adjacent RNAPII peaks. Risk region 1 included, in addition, the three strongest H3K27me3 peaks in the 5-Mb region, suggesting that some polycomb dependent repression may affect region 1 activity in LNCaP cells. The epigenomic organization of the risk regions therefore reflects multiple hotspots of active chromatin, involving RNAPII, AR occupancy and activation as well as elongation marks, but without any detectable transcriptional footprints. Thus, these features may be understood as describing enhancers that regulate either dormant transcriptional units in cis or remote active transcriptional units in trans. We note that we could not rule out the possibility of small non-coding RNAs being transcribed from the region, since RNA species shorter than 200-bp were excluded from our preparation. In order to investigate the regulatory potential of the loci exhibiting active chromatin marks, we next performed a systematic series of heterologous enhancer assays, focusing initially on defined acetylation peaks contained within the cancer risk intervals (called AcP1 through AcP15, in Figure 3).


Functional enhancers at the gene-poor 8q24 cancer-linked locus.

Jia L, Landan G, Pomerantz M, Jaschek R, Herman P, Reich D, Yan C, Khalid O, Kantoff P, Oh W, Manak JR, Berman BP, Henderson BE, Frenkel B, Haiman CA, Freedman M, Tanay A, Coetzee GA - PLoS Genet. (2009)

Enhancer-chromatin patterns on the risk regions.Epigenomic patterns at the risk intervals. Shown are the epigenomic profiles we derived for the 8q24 risk intervals. Specific regions enriched with AcH3 and AROR occupancy were isolated for further analysis (black marks labeled AcP1 to AcP15). Risk regions 1 and 3 are shown in higher resolution in the inset.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2717370&req=5

pgen-1000597-g003: Enhancer-chromatin patterns on the risk regions.Epigenomic patterns at the risk intervals. Shown are the epigenomic profiles we derived for the 8q24 risk intervals. Specific regions enriched with AcH3 and AROR occupancy were isolated for further analysis (black marks labeled AcP1 to AcP15). Risk regions 1 and 3 are shown in higher resolution in the inset.
Mentions: A higher-resolution epigenetic map of the risk regions in LNCaP is shown in Figure 3. As noted above, regions 1 and 3 were not robustly transcribed in either the normal tissues or prostate cancer cell lines. The histones in this region, however, were highly modified in LNCaP, with particular enrichment for active chromatin marks, i.e. AcH3, H3K4me1 and H3K4me3. Additionally we observed significant occupancy of AR and RNAPII. Importantly, these patterns of activity were absent from PC3, which does not express the AR. The risk regions were also enriched for the elongation mark H3K36me3; however, in line with the general lack of transcription, the H3K36me3 areas were not polarized to a specific side of adjacent RNAPII peaks. Risk region 1 included, in addition, the three strongest H3K27me3 peaks in the 5-Mb region, suggesting that some polycomb dependent repression may affect region 1 activity in LNCaP cells. The epigenomic organization of the risk regions therefore reflects multiple hotspots of active chromatin, involving RNAPII, AR occupancy and activation as well as elongation marks, but without any detectable transcriptional footprints. Thus, these features may be understood as describing enhancers that regulate either dormant transcriptional units in cis or remote active transcriptional units in trans. We note that we could not rule out the possibility of small non-coding RNAs being transcribed from the region, since RNA species shorter than 200-bp were excluded from our preparation. In order to investigate the regulatory potential of the loci exhibiting active chromatin marks, we next performed a systematic series of heterologous enhancer assays, focusing initially on defined acetylation peaks contained within the cancer risk intervals (called AcP1 through AcP15, in Figure 3).

Bottom Line: Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR).Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness.The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

View Article: PubMed Central - PubMed

Affiliation: USC/Norris Cancer Center, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.

ABSTRACT
Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

Show MeSH
Related in: MedlinePlus