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Results: 5

1.
Figure 5.

Figure 5. From: Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.

Model for the functional SNPs rs8072254 and rs1859961. The E1 enhancer within the 17q24.3 risk locus loops to the SOX9 gene. Within the E1 enhancer, the variant A allele of rs8072254 increases the binding of AR and further drives the increased enhancer activity. The variant G allele of rs1859961 decreases the binding of FOXA1 but increases the binding of AP-1. This latter increases enhancer activity. This E1 enhancer establishes a loop with the SOX9 genes in prostate cancer cells.

Xiaoyang Zhang, et al. Genome Res. 2012 August;22(8):1437-1446.
2.
Figure 3.

Figure 3. From: Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.

Candidate-functional variants within the E1 enhancer. (A) Overview of the E1 enhancer region. All SNPs from the dbSNP132 database are presented. Five are found in highly conserved regions across mammals (PhyloP value track presented) that map to the two DHS regions found in E1. The mammal basewise conservation score is presented according to their PhyloP value. (B,C) Luciferase assays using plasmids harboring the two DHS regions and either the reference or variant sequence for the five SNPs found within them. The pGL3 plasmid without the enhancer region (Empty) is used as a negative control. (Y-axis) Relative luciferase units normalized to Renilla signal ±1 SEM. The luciferase expression level for each variant SNP is compared with the plasmid homozygous for the reference alleles. The P-value is derived from a t-test; (*) p ≤ 0.05; (**) p ≤ 0.01.

Xiaoyang Zhang, et al. Genome Res. 2012 August;22(8):1437-1446.
3.
Figure 1.

Figure 1. From: Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.

Epigenetic annotation of 17q24.3 risk locus. (A) The ∼3-Mb region surrounding the PCa GWAS SNP rs1859962 presents the annotated RefSeq genes, the HapMap LD blocks relative to the rs1859962 SNP. (B) A focused view of the rs1859962 LD block presenting regulatory elements, SNPs covered by the HapMap project, and the LD score is presented. LD score: (dark red) LOD = 2, D′ = 1; (light red) LOD = 2, D′ < 1; (blue) LOD < 2, D′ = 1; (white) LOD < 2. D′ < 1. (C) The H3K4me3 enrichment from the ENCODE Project (layered for multiple cell lines) and PCa cells (LNCaP and VCaP) as well as the H3K36me3 and H3K9me3 enrichment from PCa cells (LNCaP and VCaP) are presented across the 17q24.3 PCa risk LD block. (D) DNase I-seq enrichment from LNCaP cells, H3K4me1 enrichment from the ENCODE Project (layered for multiple cell lines) and PCa cells (LNCaP and VCaP), and H3K4me2 enrichment from PCa cells (LNCaP and VCaP) are indicated. (Colored boxes) Highlight the five enhancers E1–E5 defined by these histone signatures.

Xiaoyang Zhang, et al. Genome Res. 2012 August;22(8):1437-1446.
4.
Figure 4.

Figure 4. From: Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.

The functional SNPs modulate transcription factor bindings, further imposing allele-specific gene expression. (A) The PWM matrixes of ARE DNA motif overlapping with rs8072254 are indicated. The alleles of rs8072254 are presented; (yellow) reference G allele; (green) variant A allele. (B) In vitro allele-specific AR ChIP-qPCR assay of the two alleles from rs8072254. DNA enrichment is normalized to the DNA input. (Y-axis) Relative folds of enrichment with regard to FOXA1 ± 1 SEM. The P-value is derived from a t-test; (*) p ≤ 0.05. (C) A luciferase assay was performed in PCa LNCaP cells. The experiments were transfected with control (Mock) and AR siRNA, respectively. Luciferase units were normalized to Renilla signal and further normalized to the G allele of rs8072254 ± 1 SEM. The P-value is derived from a t-test; (*) p ≤ 0.05; (N.S.) non-significant. (D) The PWM matrixes of FKH and AP-1 DNA motif overlapping with rs1859961 are indicated. The alleles of rs1859961 are presented; (green) reference A allele; (yellow) variant G allele. (E) Same as B but with regard to FOXA1 and AP-1 ChIP-qPCR assay of the two alleles from rs1859961; (*) p ≤ 0.05. (F) A luciferase assay was performed in PCa LNCaP cells. (Left panel) The experiments were transfected with Control (Mock) and FOXA1 siRNA, respectively. (Right panel) The experiments were treated with an empty control plasmid and the dominant-negative AP-1 mutant TAM67 plasmid, respectively. Luciferase units were normalized to Renilla signal, and further normalized to the A allele of rs1859961 ± 1 SEM. The P-value is derived from a t-test; (*) p ≤ 0.05; (**) p ≤ 0.01; (N.S.) non-significant.

Xiaoyang Zhang, et al. Genome Res. 2012 August;22(8):1437-1446.
5.
Figure 2.

Figure 2. From: Integrative functional genomics identifies an enhancer looping to the SOX9 gene disrupted by the 17q24.3 prostate cancer risk locus.

The E1 enhancer is connected to the SOX9 gene through a 1-Mb chromatin loop. (A) Circular representation of the 3-Mb DNA region surrounding the 17q24.3 risk locus. From inner to outside: chromatin loops identified by TaqMan probe–based 3C-qPCR in LNCaP cells (lines correspond to tested loops). (Blue) A detected loop; (gray) undetected loops. Locations of 3C primers, genes and enhancers, the LD block defined by the International HapMap Project for the rs1859962, and population expression level of nearby genes; (green) normal prostate epithelium; (red) primary prostate tumors. For gene expression, the y-axis represents the individual log2 expression level ±1 SEM. Expression levels from prostate tumors are compared with normal samples. The P-value is derived from a t-test; (***) p ≤ 0.001. Note the negative level of MAP2K6, KCNJ16, and KCNJ2 expression. (Bottom panel) Zooms into the LD block associated with rs1859962 (red bar) defining the SNPs in LD (black bars). LD score: (dark red) LOD = 2, D′ = 1; (light red) LOD = 2, D′ < 1; (blue) LOD < 2, D′ = 1; (white) LOD < 2, D′ < 1. (B) 3C-TaqMan assays with a TaqMan probe targeting the E1 enhancer. (X-axis) Genomic distance from each 3C test site to the E1 enhancer. (Y-axis) 3C interaction frequency. The SOX9 gene region is highlighted in the bottom panel. (C) Same as B but with regard to a TaqMan probe targeting the SOX9 gene. The 17q24.3 PCa risk LD block is highlighted in the bottom panel.

Xiaoyang Zhang, et al. Genome Res. 2012 August;22(8):1437-1446.

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