Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of the gene regulatory program in cancers

Abstract

Background: Most cancer alterations occur in the noncoding portion of the human genome, which contains important regulatory regions acting as genetic switches to ensure gene expression occurs at correct times and intensities in correct tissues. However, large scale discovery of noncoding events altering the gene expression regulatory program has been limited to a few examples with high recurrence or high functional impact. Results:We focused on transcription factor binding sites (TFBSs) that show similar mutation loads than what is observed in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluated the combined effects of transcriptional and post-transcriptional alteration on the dysregulation of the regulatory programs in cancer. The analysis of seven cancer cohorts culminated with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that were associated with a cascading trans-effect deregulation on the cells' regulatory program. Our analyses of cisregulatory mutations associated with miRNAs recurrently predicted 17 miRNAs as pan-cancerassociated through deregulation of their target gene networks. Overall, our predictions were enriched for protein-coding and miRNA genes previously annotated as cancer drivers. Functional enrichment analyses highlighted that cis-regulatory mutations are associated with the dysregulation of key pathways associated with carcinogenesis Conclusions: These pan-cancer results suggest that our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. It highlights how the gene regulatory program is disrupted in cancer cells by combining transcriptional and post-transcriptional regulation of gene expression.At the post-transcriptional level, miRNAs control gene expression by acting as 'buffers' to induce translational repression and mRNA degradation [28,29]. miRNA biogenesis generally comprises

Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers

“…Nevertheless, they provide the necessary background for large-scale analysis and these regions have been identified as TF-bound in biological contexts. Furthermore, the TFBSs stored in UniBind represent evolutionarily conserved elements [25] and harbour similar mutational load than protein-coding exons (using TCGA somatic mutation data), supporting their functional relevance [55].…”

Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers

“…Nevertheless, they provide the necessary background for large-scale analysis and these regions have been identified as TF-bound in biological contexts. Furthermore, the TFBSs stored in UniBind represent evolutionarily conserved elements [ 29 ] and harbour similar mutational load than protein-coding exons (using TCGA somatic mutation data), supporting their functional relevance [ 59 ].…”

UniBind: maps of high-confidence direct TF-DNA interactions across nine species

“…ChIP-eat was initially applied to 1,983 ChIP-seq peak datasets for 232 human TFs to provide a map of direct TF-DNA interactions in the human genome, which contained >8 million TFBSs stored in the UniBind database [14] . This collection of human TFBSs was proven useful to analyze cis-regulatory alterations in cancers [19][20][21] and other complex diseases [22,23] .…”