Abstract
Background
We aim to address one question: do cancer vs. normal tissue cells execute their transcription regulation essentially the same or differently, and why?
Methods
We utilized an integrated computational study of cancer epigenomes and transcriptomes of 10 cancer types, by using penalized linear regression models to evaluate the regulatory effects of DNA methylations on gene expressions.
Results
Our main discoveries are: (i) 56 genes have their expressions consistently regulated by DNA methylation specifically in cancer, which enrich pathways associated with micro-environmental stresses and responses, particularly oxidative stress; (ii) the level of involvement by DNA methylation in transcription regulation increases as a cancer advances for majority of the cancer types examined; (iii) transcription regulation in cancer vs. control tissue cells are substantially different, with the former being largely done through direct DNA methylation and the latter mainly done via transcriptional factors; (iv) the altered DNA methylation landscapes in cancer vs. control are predominantly accomplished by DNMT1, TET3 and CBX2, which are predicted to be the result of persistent stresses present in the intracellular and micro-environments of cancer cells, which is consistent with the general understanding about epigenomic functions.
Conclusions
Our integrative analyses discovered that a large class of genes is regulated via direct DNA methylation of the genes in cancer, comparing to TFs in normal cells. Such genes fall into a few stress and response pathways. As a cancer advances, the level of involvement by direct DNA methylation in transcription regulation increases for majority of the cancer types examined.
Article PDF
Similar content being viewed by others
References
Jaenisch, R. and Bird, A. (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet., 33, 245–254
Grativol, C., Hemerly, A. S. and Ferreira, P. C. G. (2012) Genetic and epigenetic regulation of stress responses in natural plant populations. Biochim. Biophys. Acta, 1819, 176–185
Seong, K.-H., Li, D., Shimizu, H., Nakamura, R. and Ishii, S. (2011) Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell, 145, 1049–1061
Ajonijebu, D. C., Abboussi, O., Russell, V. A., Mabandla, M. V. and Daniels, W. M. U. (2017) Epigenetics: a link between addiction and social environment. Cell. Mol. Life Sci., 74, 2735–2747
Wang, Y., Liu, H. and Sun, Z. (2017) Lamarck rises from his grave: parental environment-induced epigenetic inheritance in model organisms and humans. Biol. Rev., 92, 2084–2111
Feinberg, A. P. and Vogelstein, B. (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature, 301, 89–92
Esteller, M. (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene, 21, 5427–5440
Calderwood, S. K., Khaleque, M. A., Sawyer, D. B. and Ciocca, D. R. (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem. Sci., 31, 164–172
Yadav, R. K., Chae, S. W., Kim, H. R. and Chae, H. J. (2014) Endoplasmic reticulum stress and cancer. J. Cancer Prev., 19, 75–88
Cairns, R. A., Harris, I. S. and Mak, T. W. (2011) Regulation of cancer cell metabolism. Nat. Rev. Cancer, 11, 85–95
Deaton, A. M. and Bird, A. (2011) CpG islands and the regulation of transcription. Genes Dev., 25, 1010–1022
Newell-Price, J., Clark, A. J. and King, P. (2000) DNA methylation and silencing of gene expression. Trends Endocrinol. Metab., 11, 142–148
Jones, P. A. (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet., 13, 484–492
Jjingo, D., Conley, A. B., Yi, S. V., Lunyak, V. V. and Jordan, I. K. (2012) On the presence and role of human gene-body DNA methylation. Oncotarget, 3, 462–474
Bird, A. (2002) DNA methylation patterns and epigenetic memory. Genes Dev., 16, 6–21
Holm, S. (1979) A simple sequentially rejective multiple test procedure. Scand. J. Stat., 6, 65–70
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA, 102, 15545–15550
Gerlach, J. Q., Sharma, S., Leister, K. J., Joshi, L. (2012) A Tight-Knit Group: Protein Glycosylation, Endoplasmic Reticulum Stress and the Unfolded Protein Response. In Endoplasmic Reticulum Stress in Health and Disease. Agostinis P., Afshin S. eds., pp. 23–39 Dordrecht: Springer
Nguyen, T., Nioi, P. and Pickett, C. B. (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem., 284, 13291–13295
Chiarugi, P., Pani, G., Giannoni, E., Taddei, L., Colavitti, R., Raugei, G., Symons, M., Borrello, S., Galeotti, T. and Ramponi, G. (2003) Reactive oxygen species as essential mediators of cell adhesion J. Cell Biol., 161, 933–944
Salim, S. (2017) Oxidative stress and the central nervous system. J. Pharmacol. Exp. Ther., 360, 201–205
Theccanat, T., Philip, J. L., Razzaque, A. M., Ludmer, N., Li, J., Xu, X. and Akhter, S. A. (2016) Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4. Cell. Signal., 28, 190–203
Sun, H., Zhang, C., D, N., Sheng, T., and Xu, Y. (2017). Fenton Reactions Drive Nucleotide and ATP Syntheses in Cancer., (In review).
Stern, S., Fridmann-Sirkis, Y., Braun, E. and Soen, Y. (2012) Epigenetically heritable alteration of fly development in response to toxic challenge. Cell Reports, 1, 528–542
Cao, S., Zhu, X., Zhang, C., Qian, H., Schuttler, H. B., Gong, J. P., and Xu, Y. (2017) Competition between DNA methylation, nucleotide synthesis and anti-oxidation in cancer versus normal tissues. doi: 10.1158/0008-5472.CAN-17-0262
Valente, S., Liu, Y., Schnekenburger, M., Zwergel, C., Cosconati, S., Gros, C., Tardugno, M., Labella, D., Florean, C., Minden, S., et al. (2014) Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells. J. Med. Chem., 57, 701–713
Rasmussen, K. D. and Helin, K. (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev., 30, 733–750
Wee, S., Dhanak, D., Li, H., Armstrong, S. A., Copeland, R. A., Sims, R., Baylin, S. B., Liu, X. S. and Schweizer, L. (2014) Targeting epigenetic regulators for cancer therapy. Ann. N. Y. Acad. Sci., 1309, 30–36
Khansari, N., Shakiba, Y. and Mahmoudi, M. (2009) Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat. Inflamm. Allergy Drug Discov., 3, 73–80
Reuter, S., Gupta, S. C., Chaturvedi, M. M. and Aggarwal, B. B. (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med., 49, 1603–1616
Fiaschi, T. and Chiarugi, P. (2012) Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. Int. J. Cell Biol., 2012, 762825
Zhang, C., Cao, S., Toole, B. P. and Xu, Y. (2015) Cancer may be a pathway to cell survival under persistent hypoxia and elevated ROS: a model for solid-cancer initiation and early development. Int. J. Cancer, 136, 2001–2011
Thomas, C., Mackey, M. M., Diaz, A. A. and Cox, D. P. (2009) Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep., 14, 102–108
The Cancer Genome Atlas Research Network, Weinstein, J. N., Collisson, E. A., Mills, G. B., Shaw, K. R., Ozenberger, B. A., Ellrott, K., Shmulevich, I., Sander, C. and Stuart, J. M. (2013) The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet., 45, 1113–1120
Bibikova, M., Barnes, B., Tsan, C., Ho, V., Klotzle, B., Le, J. M., Delano, D., Zhang, L., Schroth, G. P., Gunderson, K. L., et al. (2011) High density DNA methylation array with single CpG site resolution. Genomics, 98, 288–295
Jiang, C., Xuan, Z., Zhao, F. and Zhang, M. Q. (2007) TRED: a transcriptional regulatory element database, new entries and other development. Nucleic Acids Res., 35, D137–D140
Neph, S., Stergachis, A. B., Reynolds, A., Sandstrom, R., Borenstein, E. and Stamatoyannopoulos, J. A. (2012) Circuitry and dynamics of human transcription factor regulatory networks. Cell, 150, 1274–1286
The ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57–74
Marbach, D., Lamparter, D., Quon, G., Kellis, M., Kutalik, Z. and Bergmann, S. (2016) Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases. Nat. Methods, 13, 366–370
Han, H., Shim, H., Shin, D., Shim, J. E., Ko, Y., Shin, J., Kim, H., Cho, A., Kim, E., Lee, T., et al. (2015) TRRUST: a reference database of human transcriptional regulatory interactions. Sci. Rep., 5, 11432
Acknowledgement
The authors would like to thank Dr. Victor Olman, formerly of the University of Georgia, for helpful discussion.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Cao, S., Zhou, Y., Wu, Y. et al. Transcription regulation by DNA methylation under stressful conditions in human cancer. Quant Biol 5, 328–337 (2017). https://doi.org/10.1007/s40484-017-0129-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40484-017-0129-y