Druliner Brooke R, Vera Daniel, Johnson Ruth, Ruan Xiaoyang, Apone Lynn M, Dimalanta Eileen T, Stewart Fiona J, Boardman Lisa, Dennis Jonathan H
Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Oncotarget. 2016 Mar 22;7(12):13429-45. doi: 10.18632/oncotarget.6811.
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.
染色质结构改变是癌症的一个标志，而染色质结构的不当调控可能代表了细胞转化的起源。重要的研究已经在全基因组范围内绘制了人类核小体分布图谱，但染色质结构在癌症进展中的作用尚未得到探讨。我们开发了一种微球菌核酸酶-转录起始位点序列捕获方法（mTSS-seq），以在原发性人类肺癌和结肠腺癌组织中全基因组范围内绘制人类转录起始位点处的核小体分布。在此，我们证实核小体重新分布是肺癌（LAC）和结肠直肠癌（CRC）腺癌中早期普遍存在的事件。这些改变的核小体结构在LAC和CRC患者样本之间是一致的，表明它们可能作为重要的早期腺癌标志物。我们证明核小体改变是由潜在的DNA序列驱动的，并增强了转录因子的结合。我们得出结论，DNA指导的核小体重新分布在癌症进展早期广泛存在。我们提出了一种全新的染色质介导的基因组调控分层模型。
