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Pan-cancer predictions of transcription factors mediating aberrant DNA methylation

ABSTRACT: Aberrant DNA methylation is a hallmark of cancer cells. However, the mechanisms underlying changes in DNA methylation remain elusive. Transcription factors initially thought to be repressed from binding by DNA methylation, have recently emerged as being able to shape DNA methylation patterns. Here, we integrated the massive amount of data available from The Cancer Genome Atlas to predict transcription factors drivingAQ1 aberrant DNA methylation in 13 cancer types. We identified differentially methylated regions between cancer and matching healthy samples, searched for transcription factor motifs enriched in those regions and selected transcription factors with corresponding changes in gene expression. We predict transcription factors known to be involved in cancer as well as novel candidates to drive hypo-methylated regions such as FOXA1 and GATA3 in breast cancer, FOXA1 and TWIST1 in prostate cancer and NFE2L2 in lung cancer. We also predict transcription factors that lead to hyper-methylated regions upon transcription factor loss such as EGR1 in several cancer types. Finally, we validate that FOXA1 and GATA3 mediate hypo-methylated regions in breast cancer cells. Our work highlights the importance of some transcription factors as upstream regulators shaping DNA methylation patterns in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167870 | GEO | 2022/03/16

REPOSITORIES: GEO

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Project description:We report the application of MeDIP sequencing technology for high-throughput profiling of M2 and M1 phenotype U937 cells. A total of 260 differentially methylated regions (DMRs) within promotor regions were identified, with 191 hyper-methylated and 69 hypo-methylated every chromosome. These DMRs were then further examined using GO analysis, with the top10 most enriched GO terms for both the hyper- and hypo-methylation groups isolated. The processes associated with hyper-methylation included the regulation of protein processes (targeting, processing, maturation and localization) and tyrosine phosphorylation of STAT5 protein, while the hypo-methylated processes included the regulation of epithelial to mesenchymal transition, mesenchymal cell differentiation and epithelial to mesenchymal transition. When further analyzing the regulation of tyrosine STAT5 phosphorylation, three associated genes (IL-31RA, IL-3, and NF2) previous shown to be associated with tumor or cancer development were also identified, thus suggesting that hyper-methylation may be important during M2 polarization into M1 cells. The epithelial to mesenchymal transition (EMT) process has been long accepted to be associated with cancer metastasis and malignance. Herein, four genes (TGFB1I1, TWIST1, HPN, and PHLDB2) that have been previously reported to participate in cancer invasion and metastasis were hypo-methylated during the EMT process, thus suggesting that these hypo-methylation sites might be a potential therapeutic target to control cancer metastasis. Moreover, the hyper-methylation was found to be predominantly localized to membranes, including the leading edge membrane, whole membrane, endoplasmic reticulum-Golgi intermediate compartment membrane, recycling endosome membrane and ruffle membrane, whereas the hypo-methylation was predominantly localized to the cytoskeleton, cell junction and cell cortex. These findings also suggest a potential ability for epigenetic therapy due to both the membrane and cytoskeleton being feasible targets for therapeutic chemical or antibody targeting. When performing pathway enrichment analysis for the hyper-methylated genes, fatty acid biosynthesis, ubiquitin mediated proteolysis, mRNA surveillance and AMPK signaling pathways were enriched; while for the hypo-methylated genes, pathways associated with cancers, such as tight junction, VEGF signaling, cAMP signaling, proteoglycans and Ras signaling pathways were enriched during polarization from M2 to M1 cells

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Pan-cancer predictions of transcription factors mediating aberrant DNA methylation

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