The importance of enhancer methylation for epigenetic regulation of tumorigenesis in squamous lung cancer
2
조회
0
다운로드
0
인용
0
참고문헌
초록
Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often occurs in smokers. To determine the epigenetic regulatory mechanisms of tumorigenesis, we performed a genome-wide analysis of DNA methylation in tumor and adjacent normal tissues from LUSC patients. With the Infinium Methylation EPIC Array, > 850,000 CpG sites, including ~350,000 CpG sites for enhancer regions, were profiled, and the differentially methylated regions (DMRs) overlapping promoters (pDMRs) and enhancers (eDMRs) between tumor and normal tissues were identified. Dimension reduction based on DMR profiles revealed that eDMRs alone and not pDMRs alone can differentiate tumors from normal tissues with the equivalent performance of total DMRs. We observed a stronger negative correlation of LUSC-specific gene expression with methylation for enhancers than promoters. Target genes of eDMRs rather than pDMRs were found to be enriched for tumor-associated genes and pathways. Furthermore, DMR methylation associated with immune infiltration was more frequently observed among enhancers than promoters. Our results suggest that methylation of enhancer regions rather than promoters play more important roles in epigenetic regulation of tumorigenesis and immune infiltration in LUSC.
Abstract
Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often occurs in smokers. To determine the epigenetic regulatory mechanisms of tumorigenesis, we performed a genome-wide analysis of DNA methylation in tumor and adjacent normal tissues from LUSC patients. With the Infinium Methylation EPIC Array, > 850,000 CpG sites, including ~350,000 CpG sites for enhancer regions, were profiled, and the differentially methylated regions (DMRs) overlapping promoters (pDMRs) and enhancers (eDMRs) between tumor and normal tissues were identified. Dimension reduction based on DMR profiles revealed that eDMRs alone and not pDMRs alone can differentiate tumors from normal tissues with the equivalent performance of total DMRs. We observed a stronger negative correlation of LUSC-specific gene expression with methylation for enhancers than promoters. Target genes of eDMRs rather than pDMRs were found to be enriched for tumor-associated genes and pathways. Furthermore, DMR methylation associated with immune infiltration was more frequently observed among enhancers than promoters. Our results suggest that methylation of enhancer regions rather than promoters play more important roles in epigenetic regulation of tumorigenesis and immune infiltration in LUSC.
참고문헌 (47)
- Travis, W. D., "The 2015 World Health Organization classification of lung tumors : impact of genetic, clinical and radiologic advances since the 2004 classification", J. Thorac. Oncol, 10, pp.1243~1260 (2015)
- Desrichard, A., "Tobacco smoking-associated alterations in the immune microenvironment of squamous cell carcinomas", J. Natl Cancer Inst, 110, pp.1386~1392 (2018)
- Kenfield, S. A., "Comparison of aspects of smoking among the four histological types of lung cancer", Tob. Control, 17, pp.198~204 (2008)
- Derman, B. A., "Treatment of advanced squamous cell carcinoma of the lung : a review", Transl. Lung Cancer Res, 4, pp.524~532 (2015)
- Pramod Darvin, "Immune checkpoint inhibitors: recent progress and potential biomarkers", Experimental and Molecular Medicine, 50, pp.1~11 (2018), 생화학분자생물학회
- Shi, Y. X., "Genome-wide DNA methylation profiling reveals novel epigenetic signatures in squamous cell lung cancer", BMC Genomics, 18, pp.901~ (2017)
- Aran, D., "DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes", Genome Biol, 14, pp.R21~ (2013)
- Bell, R. E., "Enhancer methylation dynamics contribute to cancer plasticity and patient mortality", Genome Res, 26, pp.601~611 (2016)
- Moran, S., "Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences", Epigenomics, 8, pp.389~399 (2016)
- Assenov, Y., "Comprehensive analysis of DNA methylation data with RnBeads", Nat. Methods, 11, pp.1138~1140 (2014)
- Fortin, J. P., "Preprocessing, normalization and integration of the Illumina HumanMethylationEPIC array with minfi", Bioinformatics, 33, pp.558~560 (2017)
- Lee, S., "Korean Variant Archive(KOVA) : a reference database of genetic variations in the Korean population", Sci. Rep, 7, pp.4287~ (2017)
- Kim, K., "Chromatin structure-based prediction of recurrent noncoding mutations in cancer", Nat. Genet, 48, pp.1321~1326 (2016)
- Pruitt, K. D., "The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes", Genome Res, 19, pp.1316~1323 (2009)
- Bolger, A. M., "Trimmomatic: a flexible trimmer for Illumina sequence data", Bioinformatics, 30, pp.2114~2120 (2014)
- Dobin, A., "STAR: ultrafast universal RNA-seq aligner", Bioinformatics, 29, pp.15~21 (2013)
- Harrow, J., "GENCODE: the reference human genome annotation for The ENCODE Project", Genome Res, 22, pp.1760~1774 (2012)
- Liao, Y., "FeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features", Bioinformatics, 30, pp.923~930 (2014)
- Love, M. I., "Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2", Genome Biol, 15, pp.550~ (2014)
- Yuan, H., "CancerSEA : a cancer single-cell state atlas", Nucleic Acids Res, 47, pp.D900~D908 (2019)
- Lever, J., "CancerMine: a literature-mined resource for drivers, oncogenes and tumor suppressors in cancer", Nat. Methods, 16, pp.505~507 (2019)
- Matthews, L., "Reactome knowledgebase of human biological pathways and processes", Nucleic Acids Res, 37, pp.D619~D622 (2009)
- Wang, C., "Systematic identification of genes with a cancer-testis expression pattern in 19 cancer types", Nat. Commun, 7, pp.10499~ (2016)
- Hnisz, D., "Super-enhancers in the control of cell identity and disease", Cell, 155, pp.934~947 (2013)
- Buniello, A., "The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019", Nucleic Acids Res, 47, pp.D1005~D1012 (2019)
- Rusk, N., "Expanded CIBERSORTx", Nat. Methods, 16, pp.577~ (2019)
- Zhou, W., "DNA methylation loss in late-replicating domains is linked to mitotic cell division", Nat. Genet, 50, pp.591~602 (2018)
- Ehrlich, M., "DNA hypomethylation in cancer cells", Epigenomics, 1, pp.239~259 (2009)
- Zhao, S. G., "The DNA methylation landscape of advanced prostate cancer", Nat. Genet, 52, pp.778~789 (2020)
- Dorsam, R. T., "G-protein-coupled receptors and cancer", Nat. Rev. Cancer, 7, pp.79~94 (2007)
- 박혜정, "Keratinization of Lung Squamous Cell Carcinoma Is Associated with Poor Clinical Outcome", Tuberculosis and Respiratory Diseases, 80(2), pp.179~186 (2017), 대한결핵및호흡기학회
- Baxter, E., "Epigenetic regulation in cancer progression", Cell Biosci, 4, pp.45~ (2014)
- Shintani, Y., "Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling", Am. J. Respir. Cell Mol. Biol, 38, pp.95~104 (2008)
- Specks, U., "Increased expression of type VI collagen in lung fibrosis", Am. J. Respir. Crit. Care Med, 151, pp.1956~1964 (1995)
- Umeda, Y., "Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients", Oncogene, 36, pp.6432~6445 (2017)
- Lee, S., "Surfactant protein B suppresses lung cancer progression by inhibiting secretory phospholipase A2 activity and arachidonic acid production", Cell Physiol. Biochem, 42, pp.1684~1700 (2017)
- Mitsuhashi, A., "Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages", Am. J. Pathol, 182, pp.1843~1853 (2013)
- Gibbs, Z. A., "Emerging contributions of cancer", testis antigens to neoplastic behaviors, 2018, pp.4, 701~712
- Heyn, H., "Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer", Genome Biol, 17, pp.11~ (2016)
- Schulz, H., "Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus", Nat. Commun, 8, pp.1511~ (2017)
- Voisin, S., "Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers", Genome Med, 7, pp.103~ (2015)
- Aran, D., "DNA methylation of transcriptional enhancers and cancer predisposition", Cell, 154, pp.11~13 (2013)
- Cho Jae-Won, "Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer", Experimental and Molecular Medicine, 52, pp.1~14 (2020), 생화학분자생물학회[DOI]
- Spranger, S., "Impact of oncogenic pathways on evasion of antitumour immune responses", Nat. Rev. Cancer, 18, pp.139~147 (2018)
- Conway, J. R., "Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine", Genome Med, 10, pp.93~ (2018)
- Jung, H., "DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load", Nat. Commun, 10, pp.4278~ (2019)
- Sur, I., "The role of enhancers in cancer", Nat. Rev. Cancer, 16, pp.483~493 (2016)