MYC and AP-1 oncogenes cooperatively bind enhancers to rewire transcription

Area of Science:

• Molecular Biology
• Cancer Research
• Genomics

Background:

• The transcription factor c-MYC (MYC) is frequently deregulated in human cancers.
• MYC plays a critical role in regulating cell proliferation, apoptosis, and differentiation.

Purpose of the Study:

• To investigate novel binding interactions of MYC beyond its canonical EBOX motif.
• To understand how MYC's binding dynamics at enhancers influence gene expression in cancer.

Main Methods:

• De novo motif discovery analysis on MYC ChIP-seq datasets.
• Integration of ChIP-seq and RNA sequencing data.
• Gene Ontology analysis.

Main Results:

• Cell-type-specific co-enrichment of TRE motifs (AP-1 binding sites) with MYC's EBOX motif was identified.
• MYC binds indirectly to TRE motifs at enhancers in cooperation with AP-1 transcription factors.
• Elevated MYC levels in cancer enhance indirect binding to TRE sites, frequently associated with transcriptional repression.
• MYC utilizes TRE sites to modulate cancer hallmarks like proliferation and apoptosis.

Conclusions:

• MYC's indirect binding to TRE sites at enhancers represents a significant mechanism for transcriptional rewiring in cancer.
• These findings offer insights into cancer-specific MYC functions and potential therapeutic targets.
• Targeting MYC-AP-1 interactions at enhancers may provide novel cancer treatment strategies.