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Comprehensive nucleosome mapping of the human genome in cancer progression

ABSTRACT: Altered chromatin structure is a hallmark of cancer, and inappropriate regulation of chromatin structure may represent the origin of transformation. Several important studies have mapped human nucleosome distributions genome wide, but the genome-wide role of chromatin structure in cancer progression has not been addressed. We developed a MNase-Sequence Capture method, mTSS-seq, to map genome-wide nucleosome distribution in primary human lung and colon adenocarcinoma tissue. Here, we confirm that nucleosome redistribution is an early, widespread event in lung (LAC) and colon (CRC) adenocarcinoma. These altered nucleosome architectures are consistent between LAC and CRC patient samples indicating that they may serve as important early adenocarcinoma markers. We demonstrate that the nucleosome alterations are driven by the underlying DNA sequence and potentiate transcription factor binding. We conclude that DNA-directed nucleosome redistributions are widespread early in cancer progression. We have proposed an entirely new hierarchical model for chromatin-mediated genome regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74340 | GEO | 2015/10/27

SECONDARY ACCESSION(S): PRJNA299770

REPOSITORIES: GEO

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Project description:Colorectal cancer is the third most common cancer worldwide, with 1.4 million people diagnosed in 2012 according to GLOBOCAN 2012. 95% of the colon cancer cases are that of adenocarcinomas. Removal of high-risk adenomas and tumors at early stage of colorectal cancer (CRC) can prevent its onset/progression into higher grades of cancer. The prognosis of colorectal cancer and the stage of diagnosis are closely correlated. 5-year survival rate is observed among 90% patients when diagnosed early and in less than 10% when the metastases develop. This makes the implementation of screening methods aimed at early detection paramount for reduced incidence and mortality rate. Adenocarcinomas are the cancers originating from the gland forming cells of the colon and rectal lining and are known to be the most common type of colorectal cancer. The current diagnosis options for colorectal cancers are limited to biopsy, stool tests and other laboratory tests, barium enema based imaging and other imaging techniques, colonoscopy and other endoscopic procedures which are time consuming. In this study, we used proteomics approach with an aim to identify protein biomarkers which can aid in early detection of colon adenocarcinomas to be precise. Proteins from tumor tissue of colon adenocarcinoma subjects (n=11) and their matched controls were subjected to 4-plex iTRAQ labelling followed by off-gel fractionation prior to LC-MS/MS run. The mass spectrometry data was analysed independently using two different analysis software - Spectrum Mill (SM) and Trans Proteome Pipeline (TPP). The proteins identified using either SM and/or TPP were subjected to pathway analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8 and the proteins common between the two analyses were compared with the data from CPTAC portal and Human Protein Atlas. The expression level of the shortlisted panel of proteins was studied in brain cancers as a non-colon adenocarcinoma control group and validated using MRM approach. A list of 285 unique proteins was identified to be significantly dysregulated in colon adenocarcinoma as compared to its matched controls. These proteins were found to be involved in glycolysis, pentose phosphate pathway, biosynthesis of amino acids, protein processing, spliceosome, proteosome, focal adhesion and proteoglycans in cancer. 94 of the 285 proteins were identified by both- SM and TPP. 34 of these 94 proteins were found to be dysregulated with same trend as that in data reported on CPTAC portal and 9 of these 34 proteins were validated using MRM approach. The proteins identified from this study could be validated further to investigate the role of these proteins as potential biomarkers for early detection of colon adenocarcinoma.

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Comprehensive nucleosome mapping of the human genome in cancer progression

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