Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Epigenomic enhancer profiling defines a signature of colon cancer [ChIP-seq]

ABSTRACT: Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, despite the fact that distal regulatory elements play a central role in controlling transcription patterns. Here we utilize 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 unique transcriptional program to promote colon carcinogenesis. Examination of 3 histone modifications and global expression data in primary colon cancer cell lines and normal colon crypt controls

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Scacheri

PROVIDER: E-GEOD-36204 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Epigenomic enhancer profiling defines a signature of colon cancer.

Akhtar-Zaidi Batool B Cowper-Sal-lari Richard R Corradin Olivia O Saiakhova Alina A Bartels Cynthia F CF Balasubramanian Dheepa D Myeroff Lois L Lutterbaugh James J Jarrar Awad A Kalady Matthew F MF Willis Joseph J Moore Jason H JH Tesar Paul J PJ Laframboise Thomas T Markowitz Sanford S Lupien Mathieu M Scacheri Peter C PC

Science (New York, N.Y.) 20120412 6082

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 col ...[more]

PMID: 22499810

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Project description:Goal: Since disease susceptibility of the intestine exhibits an anatomical bias, we propose that the chromatin landscape, especially the site-specific epigenetic differences in histone modification patterns throughout the longitudinal axis, contributes to a differential response to chemoprotective agents. Method: We assessed the chromatin structure associated with gene expression profiles in the rat proximal and distal colon by globally correlating chromatin immunoprecipitation next-generation sequencing analysis (ChIP-Seq) with mRNA transcription (RNA-Seq) data. Crypts were isolated from the proximal and distal colonic regions from rats maintained on a semi-purified diet, and mRNA gene expression profiles were generated using RNA-Seq. The remaining isolated crypts were paraformaldehyde-crosslinked and chromatin immunoprecipitated using antibodies against H3K4me3, H3K9me3, and RNA Polymerase II. Results/Conclusion: Globally, RNA-Seq results indicated that 9,866 genes were actively expressed, of which 540 genes were differentially expressed between the proximal and distal colon. With regard to differentially expressed genes, a high correlation was observed between H3K4me3-Seq and RNA-Seq data, with 96% of the canonical pathways being similarly affected in the H3K4me3-Seq and RNA-Seq data sets. Gene ontology analysis indicated that colonic crypt location significantly impacted both chromatin and transcriptional regulation of genes involved in cell transformation, lipid metabolism, lymphatic development and immune cell trafficking. Gene function analysis indicated that the PI3-Kinase signaling pathway was regulated in a site-specific manner, e.g., pathway proto-oncogenes, c-Jun, c-Fos and ATF, were up-regulated in the distal colon. Middle and long non-coding RNAs (lncRNAs) were also detected in the colon, including select lncRNAs formerly only detected in the rat nervous system. In summary, distinct combinatorial patterns of histone modifications exist in the proximal versus distal colon. These site-specific differences may explain the differential effects of chemoprotective agents on cell transformation in the ascending (proximal) and descending (distal) colon. Examination of mRNA profiles and 2 different histone modifications (H3K4me3 and H3K9me3) in 2 tissue types (proximal and distal colon).

Dataset Information

Epigenomic enhancer profiling defines a signature of colon cancer [ChIP-seq]

Publications

Epigenomic enhancer profiling defines a signature of colon cancer.

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