Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks
- Jin Li1,2,3,14,
- Yan Li1,2,3,14,
- Wei Li1,2,3,14,
- Huaibing Luo1,2,3,14,
- Yanping Xi1,2,3,14,
- Shihua Dong1,2,3,14,
- Ming Gao4,5,14,
- Peng Xu1,2,3,
- Baolong Zhang1,2,3,
- Ying Liang1,2,3,
- Qingping Zou1,2,3,
- Xin Hu6,
- Lina Peng1,2,3,
- Dan Zou4,5,
- Ting Wang7,8,
- Hongbo Yang9,10,
- Cizhong Jiang11,
- Shaoliang Peng4,5,
- Feizhen Wu12,13 and
- Wenqiang Yu1,2,3
- 1Shanghai Public Health Clinical Center and Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Laboratory of RNA Epigenetics, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 201508, China;
- 2Department of Biochemistry and Molecular Biology, Shanghai Medical College, Key Laboratory of Ministry of Education, Department of Molecular Biology, Fudan University, Shanghai, 200032, China;
- 3Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200433, China;
- 4College of Computer Science and Electronic Engineering and National Supercomputing Centre in Changsha, Hunan University, Changsha 410082, China;
- 5School of Computer Science, National University of Defense Technology, Changsha, 410073, China;
- 6Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China;
- 7Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
- 8Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA;
- 9Department of Biochemistry and Molecular Biology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania 17033, USA;
- 10Bioinformatics and Genomics Program, The Pennsylvania State University, University Park, Pennsylvania 16802, USA;
- 11Institute of Translational Research, Tongji Hospital, the School of Life Sciences and Technology, Shanghai Key Laboratory of Signaling and Disease Research, the Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, 200092, China;
- 12Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- 13Children's Hospital of Fudan University, Shanghai, 201102, China
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↵14 These authors contributed equally to this work.
Abstract
Aberrant DNA methylation is a distinguishing feature of cancer. Yet, how methylation affects immune surveillance and tumor metastasis remains ambiguous. We introduce a novel method, Guide Positioning Sequencing (GPS), for precisely detecting whole-genome DNA methylation with cytosine coverage as high as 96% and unbiased coverage of GC-rich and repetitive regions. Systematic comparisons of GPS with whole-genome bisulfite sequencing (WGBS) found that methylation difference between gene body and promoter is an effective predictor of gene expression with a correlation coefficient of 0.67 (GPS) versus 0.33 (WGBS). Moreover, Methylation Boundary Shift (MBS) in promoters or enhancers is capable of modulating expression of genes associated with immunity and tumor metabolism. Furthermore, aberrant DNA methylation results in tissue-specific enhancer switching, which is responsible for altering cell identity during liver cancer development. Altogether, we demonstrate that GPS is a powerful tool with improved accuracy and efficiency over WGBS in simultaneously detecting genome-wide DNA methylation and genomic variation. Using GPS, we show that aberrant DNA methylation is associated with altering cell identity and immune surveillance networks, which may contribute to tumorigenesis and metastasis.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.240606.118.
- Received June 16, 2018.
- Accepted December 18, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
