TSProm: Deciphering the Genomic Context of Tissue Specificity

Area of Science:

• Genomics
• Computational Biology
• Epigenetics

Background:

• Tissue-specific (TSp) gene expression is vital for development and disease.
• Traditional methods miss regulatory information in non-coding DNA.
• Distal promoter regions contain crucial regulatory grammar.

Purpose of the Study:

• Introduce TSProm, a framework using DNA foundation models (DNABERT2) to decode TSp promoter regulatory logic.
• Isolate sequence motifs defining tissue identity using comparative model training.
• Provide interpretable AI (xAI) for robust feature interpretation.

Main Methods:

• Specialized DNA foundation model (DNABERT2) for TSp promoter analysis.
• Comparative training of two models: general promoter biology (A) and TSp regulation (B).
• Integrated xAI module with attention-based discovery and SHAP analysis.

Main Results:

• Identified clinically relevant transcription factors (TFs) in brain promoters (SP1, MYC, HES6).
• Validated TF roles in brain-related diseases like gliomas and neuroblastomas.
• Revealed C2H2 Zinc Finger proteins as dominant in TSp gene regulation.

Conclusions:

• TSProm offers a novel, interpretable framework for identifying TSp gene regulatory elements.
• Provides powerful computational tools for studying TSp gene regulation in normal and disease states.
• Advances understanding of the regulatory grammar in non-coding DNA.