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. 2012 May 11;336(6082):736-9.
doi: 10.1126/science.1217277. Epub 2012 Apr 12.

Epigenomic Enhancer Profiling Defines a Signature of Colon Cancer

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Free PMC article

Epigenomic Enhancer Profiling Defines a Signature of Colon Cancer

Batool Akhtar-Zaidi et al. Science. .
Free PMC article

Abstract

Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, even though distal regulatory elements play a central role in controlling transcription patterns. We used the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome-wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly predictive of the in vivo colon cancer transcriptome. Furthermore, VELs are enriched in haplotype blocks containing colon cancer genetic risk variants, implicating these genomic regions in colon cancer pathogenesis. We propose that reproducible changes in the epigenome at enhancer elements drive a specific transcriptional program to promote colon carcinogenesis.

Figures

Figure 1
Figure 1
H3K4me1 ChIP-seq identifies Variant Enhancer Loci (VELs). (A) UCSC browser views of H3K4me1 profiles from 3 normal crypts and a CRC cell line (V400), illustrating an example of a gained (left) and a lost (right) VEL. Heatmaps show the corresponding H3K4me1 ChIP-seq signals +/-5kb of VEL midpoints. (B) Number of VELs and unchanged H3K4me1-sites in CRC samples relative to normal controls. (D) Number of unique and common VELs. (D) Distribution of VELs among CRC lines. Blue = VEL. (E) Percentage of control enhancers and VELs that overlap with H3K4me1 sites in any of nine non-colon cell types. All comparisons are significant by Chi Squared test (P < 10e-10).
Figure 2
Figure 2
VELs correlate with aberrant gene expression. (A) Fold change in expression of VEL and control genes for a representative CRC line (V400). Number of (B) gained and (C) lost VELs associated with over-expressed and repressed genes, respectively. Fold change in expression of genes associated with variable numbers of (D) gained VELs and (E) lost VELs in CRC sample V400. (F) Levels of all genes (grey) and aberrantly expressed genes (> 1.5-fold relative to crypts) associated with VELs in CRC sample V400.
Figure 3
Figure 3
Common VELs predict aberrant gene expression in primary tumors. (A) (left) Red bars represent the percentage of overexpressed genes associated with gained VELs common to five or more lines (G5-G9) that validate as overexpressed in primary tumors. Black bars represent the baseline predictive power when the VEL is not considered, i.e., the percentage of overexpressed genes in 5 or more cell lines that validate as overexpressed in primary tumors. G9 genes that validated as overexpressed in primary tumors are listed in brackets. (right) same as left, but for lost VELs common to six or more lines (L6-L9). (B) Heatmap of expression of VEL-associated genes in panel A (red and blue bars) in normal colon tissue (n=16) and primary CRC tumors (n=120). (C) UCSC Browser view of H4K4me1 ChIP-seq signals across the PDGH locus, associated with a lost VEL common to 6 CRC samples (highlighted in yellow).
Figure 4
Figure 4
Colon enhancers and VELs are associated with genetic risk variants for CRC. (A) Results of VSE analysis showing that 16 of 20 CRC-risk SNP clusters map to H3K4me1-marked enhancers in a colon crypt sample (C101, red diamond), compared to a null distribution (grey). (B) (left) The results of VSE analyses testing the association between CRC-risk SNPs and H3K4me1-sites in 10 cell types. The red line represents the significance threshold (P<0.001). The lower horizontal line represents the unadjusted significance threshold. The individual CRC SNPs found to be associated with H3K4me1-enhancers in each cell type are indicated in boxes, above each boxplot. (right) VSE analysis of the CRC-risk SNPs and VELs. Control enhancers are H3K4me1 sites that are unchanged between CRC samples and crypts. L1 corresponds to unique lost VELs; L2-L9 to losses common to 2-9 lines. G1 corresponds to unique gained VELs; G2-G9 to gains shared between 2-9 lines. (C) Example of a lost VEL directly overlapping a CRC risk SNP shown within the relevant haplotype block structure (red).

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