DNA-guided transcription factor interactions extend human gene regulatory code

Area of Science:

• Genomics
• Molecular Biology
• Systems Biology

Background:

• Transcription factors (TFs) binding to DNA form the gene regulatory code, crucial for cell fate and transcriptional programs.
• Human gene regulation is complex, involving over 1,600 interacting TFs, but the landscape of their DNA-bound interactions remains poorly defined.

Purpose of the Study:

• To map biochemical interactions between DNA-bound human transcription factors.
• To identify TF-TF binding preferences, interactions, and bound DNA sequences simultaneously.
• To discover novel composite motifs formed by interacting TF pairs.

Main Methods:

• Utilized CAP-SELEX (Cell-Array Processing - Systematic Evolution of Ligands by Exponential Enrichment), a high-throughput method.
• Screened over 58,000 transcription factor-transcription factor pairs to identify interacting pairs and their DNA binding preferences.

Main Results:

• Identified 2,198 interacting TF pairs, with 1,329 showing preferential binding to specific motif arrangements.
• Discovered 1,131 novel TF-TF composite motifs, distinct from individual TF motifs.
• Estimated that the screen identified 18% to 47% of all human TF-TF motifs.

Conclusions:

• Novel composite motifs are enriched in cell-type-specific elements, are active in vivo, and often form between developmentally co-expressed TFs.
• Interactions between TFs defining embryonic axes explain how similar TFs can specify distinct cell types along these axes.