Transcription regulation by DNA methylation under stressful conditions in human cancer

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.