p300 Is an Obligate Integrator of Combinatorial Transcription Factor Inputs

Area of Science:

• Molecular Biology
• Epigenetics
• Gene Regulation

Background:

• Transcription coactivators are crucial for gene expression but lack DNA-binding domains.
• Their recruitment to target DNA loci remains incompletely understood.
• Hypotheses include recruitment by transcription factors, histone binding, or phase separation via intrinsically disordered regions (IDRs).

Approach:

• Systematic mutation of domains in the prototypical coactivator p300.
• Single-molecule tracking in live cells to observe coactivator-chromatin interactions.
• Analysis of the impact of acetyltransferase activity and TF-interaction domains on chromatin association.

Key Points:

• Coactivator-chromatin binding relies on the combinatorial interaction of multiple TF-binding domains.
• Acetyltransferase activity negatively regulates coactivator association with chromatin.
• N-terminal TF-interaction domains modulate p300's catalytic activity.

Conclusions:

• Individual TF-interaction domains are insufficient for robust chromatin binding or activity regulation.
• Coactivator recruitment and function necessitate coordinated interactions with multiple transcription factors.
• This highlights a fundamental principle for eukaryotic gene regulation.