ONECUT2 regulates RANKL-dependent enterocyte and microfold cell differentiation in the small intestine; a multi-omics...

Area of Science:

• Immunology
• Cell Biology
• Gastroenterology

Background:

• Microfold (M) cells in Peyer's patches (PP) are crucial for intestinal immune responses by transporting antigens.
• Understanding M cell differentiation mechanisms is key to regulating gut immunity.

Purpose of the Study:

• To investigate the molecular mechanisms driving M cell differentiation using a multi-omics approach in mouse small intestinal organoids.
• To identify key transcription factors and regulatory elements involved in M cell lineage specification.

Main Methods:

• Multi-omics profiling including chromatin accessibility and transcription factor dynamics.
• Single-cell RNA sequencing to identify precursor populations.
• Development and application of the computational tool SCEPIA.
• In vitro and in vivo perturbation experiments.

Main Results:

• Identified an enterocyte and M cell precursor population.
• Uncovered high expression and motif activity of the transcription factor ONECUT2 in precursors.
• Demonstrated that ONECUT2 supports enterocyte differentiation and restricts M cell lineage specification.
• Established ONECUT2 acts downstream of the RANK/RANKL signaling axis.

Conclusions:

• ONECUT2 plays a critical role in regulating cell fate balance within the Peyer's patch epithelium.
• This study provides a molecular blueprint for understanding and potentially manipulating M cell differentiation.
• The findings offer insights into mechanisms controlling cell fate switches in the intestinal epithelium.