Defining the impact of rewiring essential transcription factor binding patterns by single nucleotide polymorphisms and DNA methylation changes in cancer (CancerDependence)

Fiche projet

Année

2025

Appel à projets

Appel à projets « Soutien à l'émergence de projets transfrontaliers » (Cancéropôle Est)

Acronyme

CancerDependence

Resumé

Abnormal gene expression patterns are a hallmark of cancer, with the loss or gain in gene activity often driven by mutations in regulatory sequences, including single nucleotide polymorphisms (SNPs), or altered epigenetic landscapes such as DNA methylation. The impact of these changes on tissue-specifically expressed genes has been extensively studied, however, how they influence regulatory networks controlled by ubiquitously expressed regulators and the role this plays in disease development and prognosis has been less well explored.

Transcription factors (TFs) are key regulatory proteins that bind specific DNA sequence motifs to control gene expression. The presence of SNPs or the gain or loss of DNA methylation at motifs can alter TF binding. SNPs have been linked to a broad range of diseases; however, they are often found in distal regulatory regions making it difficult to assign a functional consequence to individual SNPs. On the other hand, changes in DNA methylation levels at regulatory regions is a hallmark of cancer, however, again, it has been difficult to define the underlying mechanism and direct impact of these changes on gene activity.

Here we will explore how SNPs and altered DNA methylation levels in motifs for ubiquitously expressed TFs that drive the activity of cancer cell dependent genes influence gene expression. We will specifically focus on binding sites of TFs that have a well- defined motif and are sensitive to DNA methylation, for example, BANP and NRF1. This work will identify SNPs and methylation changes at BANP and NRF1 motifs in different cancer types, and link them to cancer-dependent gene expression changes. This will lay the foundation for a functional study to determine if BANP and NRF1 indeed drive the expression of the linked genes and open the door to a new therapeutic strategy where genetic and epigenetic editing could be used to reset detrimental gene expression changes and potentially also kill cancer cells.

Avec Dr Ralph GRAND (Zentrum für Molekulare Biologie der Universität Heidelberg - ZMBH, Allemagne)