Integrative Multimodal Profiling of TAp73 and DNp73 Reveals Isoform-Specific Transcriptomic Coregulator Landscapes in...

Area of Science:

• Cancer biology
• Molecular oncology
• Epigenetics

Background:

• The p73 transcription factor (TF) exhibits diverse isoforms with conflicting roles in cancer progression.
• While DNp73 promotes cancer stemness and metastasis, the tumor-suppressive TAp73 isoform can paradoxically drive cancer growth.
• Understanding how p73 isoforms with identical DNA-binding domains yield divergent functional outcomes is crucial.

Purpose of the Study:

• To comprehensively map the genome-wide DNA-binding and co-transcription factor (coTF) profiles of TAp73α and DNp73β isoforms in melanoma.
• To identify isoform-specific coTF repertoires and their functional implications in cancer hallmarks.
• To establish a framework for modeling p73 isoform influence on cancer reprogramming.

Main Methods:

• Utilized CUT&RUN assays to profile genome-wide DNA binding of TAp73α and DNp73β in melanoma cells.
• Integrated JASPAR database, transcriptomics, and proteomics data for coTF identification.
• Analyzed patient survival and gene expression data to correlate findings with clinical outcomes.

Main Results:

• Discovered distinct coTF repertoires associated with TAp73 and DNp73, revealing isoform-specific regulatory networks.
• Identified a coregulator signature for epithelial-mesenchymal transition (EMT) genes, enriched for both isoforms, with context-dependent survival effects and poor patient prognosis.
• Validated PATZ1 as a novel direct interactor of DNp73β among EMT-associated coTFs.

Conclusions:

• Generated a comprehensive reference map of p73 isoform-specific DNA binding and coTF recruitment in melanoma.
• Demonstrated that p73 isoforms orchestrate distinct transcriptional programs influencing cancer progression.
• Established a workflow for modeling p73 isoform impact on cancer, with potential applications in AI-based individualized therapies.