Pan-cancer predictions of transcription factors mediating aberrant DNA methylation

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. FOXA1 and GATA3 ChIP-seq (two replicates each) and corresponding input in HCC1954 breast cancer cells. WGBS in hTERT-HME1 normal cells and HCC1954 cancer cells as well as in FOXA1 and GATA3 KO clones (two replicates each) in HCC1954 cancer cells and with each a negative CRISPR clone.