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Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of gene regulatory

Jaime A Castro-Mondragon1, Miriam Ragle Aure2,3, Ole Christian Lingjærde2,4,5

  • 1Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, 0318 Oslo, Norway.

Nucleic Acids Research
|December 8, 2022
PubMed

Insights

Cancer mutations in noncoding DNA, specifically transcription factor binding sites (TFBSs), disrupt gene regulation. This study links TFBS mutations to altered gene expression and cancer pathways, revealing new regulatory network dysregulations.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Biology

Background:

  • Most cancer-causing genetic alterations occur in the noncoding genome, which regulates gene expression.
  • Discovering noncoding mutations that impact cellular regulatory programs has been challenging, often limited to highly recurrent or impactful mutations.

Purpose of the Study:

  • To investigate the mutation load in transcription factor binding sites (TFBSs) and compare it to protein-coding exons.
  • To analyze the combined effects of mutations in TFBSs and subsequent gene expression changes (transcriptional and post-transcriptional) on cancer regulatory programs.
  • To identify specific protein-coding and microRNA (miRNA) genes affected by TFBS mutations and their downstream regulatory consequences.

Main Methods:

  • Combined analysis of cancer somatic mutations within TFBSs and gene expression data (protein-coding and miRNA) across seven TCGA cohorts.
  • Evaluation of cis-regulatory mutations associated with miRNAs to predict their impact on target gene networks.
  • Statistical enrichment analysis to identify cancer-associated genes and pathways affected by identified mutations.

Main Results:

  • Transcription factor binding sites (TFBSs) exhibit mutation loads comparable to protein-coding exons.
  • Identification of protein-coding and miRNA genes linked to TFBS mutations, demonstrating cascading trans-effect deregulation.
  • Prediction of 12 mature miRNAs (from 7 precursors) associated with target gene network deregulation due to cis-regulatory mutations.
  • Enrichment of predictions for cancer-associated genes and pathways, highlighting the role of cis-regulatory mutations in carcinogenesis.

Conclusions:

  • Mutations in TFBSs are a significant factor in cancer regulatory program disruption.
  • The integration of transcriptional and post-transcriptional regulatory analysis effectively predicts cis-regulatory mutations impacting gene regulatory networks in cancer.
  • This approach advances the understanding of noncoding mutations in cancer pathogenesis and identifies potential therapeutic targets.

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