Abstract
Altered chromatin structure is a hallmark of cancer, and inappropriate regulation of chromatin structure may represent the origin of transformation. Important studies have mapped human nucleosome distributions genome wide, but the role of chromatin structure in cancer progression has not been addressed. We developed a MNase-Transcription Start Site Sequence Capture method (mTSS-seq) to map the nucleosome distribution at human transcription start sites genome-wide 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.
Highlights
Despite the central role of chromatin as the ultimate substrate for all nuclear events, the structure of chromatin remains poorly characterized
There have recently been a handful of extremely important studies measuring nucleosome distribution in a variety of organisms, there have been no genome-wide nucleosome distribution maps in primary patient tumors compared to their matched normal tissue [57, 9, 11, 12, 27, 41, 43]
We developed an innovative approach, mTSS-seq, to comprehensively measure genome wide nucleosome distribution changes in the progression of cancer
Summary
Despite the central role of chromatin as the ultimate substrate for all nuclear events, the structure of chromatin remains poorly characterized. A handful of seminal papers have measured genome wide human nucleosome positions in a limited number [1,2] of cell states [5,6,7,8] To address this shortcoming, we have developed a robust, cost-effective sequencing-based nucleosome distribution mapping platform to analyze chromatin structure at the transcription start site (TSS) of ~22,000 open reading frames in the human genome. We have developed a robust, cost-effective sequencing-based nucleosome distribution mapping platform to analyze chromatin structure at the transcription start site (TSS) of ~22,000 open reading frames in the human genome We have applied this approach to study the nucleosome distribution in primary patient tumor samples representing multiple stages and grades of both lung adenocarcinoma (LAC) and colorectal cancer (CRC)
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