GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional...

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Multiciliated cells (MCCs) are crucial for fluid and gamete transport in mammals.
• The Geminin family transcriptional activators GEMC1 and MCIDAS are essential for MCC differentiation.
• The precise mechanisms of transcriptional activation and functional redundancy between GEMC1 and MCIDAS are not fully understood.

Purpose of the Study:

• To investigate the transcriptional targets and protein interactions of GEMC1 and MCIDAS.
• To elucidate the role of distinct SWI/SNF subcomplexes in MCC-specific gene regulation.
• To determine the functional impact of targeting specific SWI/SNF complexes on MCC differentiation.

Main Methods:

• Comparative analysis of transcriptional targets and proximal proteomes of GEMC1 and MCIDAS.
• Identification of differential interactions with SWI/SNF subcomplexes (BAF and ncBAF).
• Functional assessment using a BRD9 inhibitor in cell-based models of MCC differentiation.

Main Results:

• GEMC1 and MCIDAS share highly similar transcriptional targets and proximal proteomes.
• GEMC1 preferentially interacts with ARID1A-containing BAF complexes, while MCIDAS interacts with BRD9-containing ncBAF complexes.
• Inhibition of BRD9 disrupted MCIDAS-mediated gene activation and impaired MCC differentiation.

Conclusions:

• Differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is critical for MCC transcriptional regulation.
• The distinct C-terminal domains of GEMC1 and MCIDAS mediate their specific interactions with SWI/SNF complexes.
• Targeting specific SWI/SNF complexes offers a potential strategy to modulate MCC differentiation.