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Whole DNA methylome profiling in lung cancer cells before and after epithelial-to-mesenchymal transition

Fatao Liu1, Yi Zhou1, Daizhan Zhou2, Mengyuan Kan1, Xiaomin Niu3, Zhou Zhang2, Di Zhang2, Liming Tao1, Lin He124, Lixing Zhan1* and Yun Liu45*

Author Affiliations

1 Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Taiyuan RD, Shanghai 200031, PR China

2 Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, PR China

3 Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, PR China

4 Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China

5 Key Laboratory of Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, 138 YiXueYuan RD, Shanghai 200032, PR China

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Diagnostic Pathology 2014, 9:66  doi:10.1186/1746-1596-9-66

Published: 20 March 2014

Abstract

Background

Metastatic lung cancer is one of the leading causes of cancer death. In recent years, epithelial-to-mesenchymal transition (EMT) has been found to contribute to metastasis, as it enables migratory and invasive properties in cancer cells. Previous genome-wide studies found that DNA methylation was unchanged during EMT induced by TGF-β in AML12 cells. In this study, we aimed to discover EMT-related changes in DNA methylation in cancer cells, which are poorly understood.

Methods

We employed a next-generation sequencing-based method, MSCC (methyl-sensitive cut counting), to investigate DNA methylation during EMT in the A549 lung cancer cell line.

Results

We found that methylation levels were highly correlated to gene expression, histone modifications and small RNA expression. However, no differentially methylated regions (DMRs) were found in A549 cells treated with TGF-β for 4 h, 12 h, 24 h and 96 h. Additionally, CpG islands (CGIs) showed no overall change in methylation levels, and at the single-base level, almost all of the CpGs showed conservation of DNA methylation levels. Furthermore, we found that the expression of DNA methyltransferase 1, 3a, 3b (DNMT1, DNMT3a, DNMT3b) and ten-eleven translocation 1 (TET1) was altered after EMT. The level of several histone methylations was also changed.

Conclusions

DNA methylation-related enzymes and histone methylation might have a role in TGF-β-induced EMT without affecting the whole DNA methylome in cancer cells. Our data provide new insights into the global methylation signature of lung cancer cells and the role of DNA methylation in EMT.

Virtual slides

The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1112892497119603 webcite

Keywords:
DNA methylation; Epithelial-to-mesenchymal transition (EMT); Lung cancer; CpG; CGI; MSCC