DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation

Abstract

Background: Prostate cancer (PCa) has the highest incidence rates of cancers in men in western countries. Unlike several other types of cancer, PCa has few genetic drivers, which has led researchers to look for additional epigenetic and transcriptomic contributors to PCa development and progression. Especially datasets on DNA methylation, the most commonly studied epigenetic marker, have recently been measured and analysed in several PCa patient cohorts. DNA methylation is most commonly associated with downregulation of gene expression. However, positive associations of DNA methylation to gene expression have also been reported, suggesting a more diverse mechanism of epigenetic regulation. Such additional complexity could have important implications for understanding prostate cancer development but has not been studied at a genome-wide scale. Results: In this study, we have compared three sets of genome-wide single-site DNA methylation data from 870 PCa and normal tissue samples with multi-cohort gene expression data from 1117 samples, including 532 samples where DNA methylation and gene expression have been measured on the exact same samples. Genes were classified according to their corresponding methylation and expression profiles. A large group of hypermethylated genes was robustly associated with increased gene expression (UPUP group) in all three methylation datasets. These genes demonstrated distinct patterns of correlation between DNA methylation and gene expression compared to the genes showing the canonical negative association between methylation and expression (UPDOWN group). This indicates a more diversified role of DNA methylation in regulating gene expression than previously appreciated. Moreover, UPUP and UPDOWN genes were associated with different compartments-UPUP genes were related to the structures in nucleus, while UPDOWN genes were linked to extracellular features. Conclusion: We identified a robust association between hypermethylation and upregulation of gene expression when comparing samples from prostate cancer and normal tissue. These results challenge the classical view where DNA methylation is always associated with suppression of gene expression, which underlines the importance of considering corresponding expression data when assessing the downstream regulatory effect of DNA methylation.

Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses

“…In this study, Fürst et al showed that increased CpG methylation of a single site alters the binding of transcriptional repressor TGIF1 to the host DNA and lowers the local histone H3 occupancy, which results in the increase of ESR1 mRNA expression. In addition, there is a growing body of evidence that DNA hypermethylation links to positive gene expression as demonstrated by a recent systemic study in prostate cancer [ 109 ], supported by other studies showing that certain transcription factors preferentially bind to methylated DNA [ 110 , 111 ]. Beyond the transcriptional level, EBV infection has the potential to trigger multiple innate immune signaling pathways.…”

Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy

“…However, the PA patients have increased DNAm at 5′ upstream of IL12B and CXCL12 , which is associated with increased IL-12β and CXCL12 protein expression compared with NA participants. It should be noted that, although gene silencing by promoter hypermethylation seems to be the most likely mode of action, there is growing evidence of a more complex view on the effect of DNAm in various contexts ( 37 – 41 ). In particular, for genes that become methylated, the associated expression level can be unaffected or even upregulated in some cases ( 40 ), suggesting a more diverse mechanism of epigenetic regulation.…”

Identification of Differentially Methylated CpG Sites in Fibroblasts from Keloid Scars

“…Of the differentially methylated 100,000 CpG sites in our analysis, more than two-thirds were hypermethylated. Consistent with several cancers-linked DNA hypermethylation, such as in prostate cancer (PCa) [ 46 ], and breast cancer [ 47 ]. In contrast, more hypomethylation profiles found in keloids genome, frequently in the non-promoter regions [ 17 ].…”