Divergence in a eukaryotic transcription factor's co-TF dependence involves multiple intrinsically disordered regions

Area of Science:

• Molecular Biology
• Genetics
• Evolutionary Biology

Background:

• Transcription factors (TFs) are crucial for eukaryotic gene regulation through combinatorial control.
• The mechanisms, evolution, and regulatory impact of TF interdependence remain incompletely understood.
• Natural variation in the yeast phosphate starvation (PHO) response provides a model to study TF genetic basis and species variation.

Purpose of the Study:

• To investigate the genetic basis and species variation in transcription factor interdependence using the yeast PHO response.
• To elucidate the role of intrinsically disordered regions (IDRs) in modulating TF activity and interdependence.
• To understand how TF IDR divergence drives the evolution of gene regulation.

Main Methods:

• Comparative analysis of TF binding affinity and gene regulation across yeast species (Saccharomyces cerevisiae and Candida glabrata).
• Application of machine learning and yeast one-hybrid assays to identify functional regions within TFs.
• Characterization of intrinsically disordered regions (IDRs) and their impact on TF activation and autoinhibition.

Main Results:

• Candida glabrata Pho4 exhibits higher DNA binding affinity and regulates more genes compared to Saccharomyces cerevisiae Pho4.
• Two intrinsically disordered regions (IDRs) in C. glabrata Pho4 enhance its activation domain activity.
• An IDR in S. cerevisiae Pho4 modulates its activity, enabling co-factor interaction and inhibiting activity in their absence.

Conclusions:

• Divergence in intrinsically disordered regions (IDRs) is a key driver in the evolution of transcription factor interdependence.
• IDR variations influence TF activation potential and autoinhibition, thereby shaping gene regulatory networks.
• This study provides insights into how TF structural evolution impacts gene regulation across species.