Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites

Area of Science:

• Developmental biology
• Molecular mechanisms of cell fate determination
• Transcription factor function

Background:

• Cellular context significantly influences transcription factor (TF) lineage determination.
• Mechanisms underlying TF functional switching remain largely unknown.

Purpose of the Study:

• Investigate how transcription factors are repurposed for different cell fates.
• Elucidate the roles of Gfi1 and Pou4f3 in Atoh1-mediated cell fate switching.

Main Methods:

• Utilized a transcriptional programming model.
• Analyzed Atoh1's regulatory targets and genomic binding profiles.
• Assessed the synergistic effects of Gfi1 and Pou4f3 on Atoh1 activity.

Main Results:

• Atoh1 was repurposed from a neuronal to an inner ear hair cell (HC) determinant by Gfi1 and Pou4f3.
• Pou4f3 facilitated Atoh1 access to sensory gene loci.
• Gfi1 exhibited dual roles: repressing antagonistic genes and co-activating Atoh1 at target genes, enhancing its activity without altering binding profile.

Conclusions:

• Gfi1 and Pou4f3 cooperatively reprogram Atoh1's lineage-determining capacity.
• Gfi1's dual repressor and co-activator functions are critical for the HC lineage switch.
• Demonstrates combinatorial control of cell identity through TF interactions and context-dependent modulation.