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

Microfold (M) cells reside in the intestinal epithelium of Peyer's patches (PP). Their unique ability to take up and transport antigens from the intestinal lumen to the underlying lymphoid tissue is key in the regulation of the gut-associated immune response. Here, we applied a multi-omics appr...

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Bibliographic Details
Published in:	Nucleic acids research Vol. 51; no. 3; pp. 1277 - 1296
Main Authors:	Luna Velez, Maria V, Neikes, Hannah K, Snabel, Rebecca R, Quint, Yarah, Qian, Chen, Martens, Aniek, Veenstra, Gert Jan C, Freeman, Michael R, van Heeringen, Simon J, Vermeulen, Michiel
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 22-02-2023
Subjects:	Animals Cell Differentiation Enterocytes Intestinal Mucosa Intestine, Small M Cells Mice Molecular Biology Multiomics Transcription Factors - metabolism
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Summary:	Microfold (M) cells reside in the intestinal epithelium of Peyer's patches (PP). Their unique ability to take up and transport antigens from the intestinal lumen to the underlying lymphoid tissue is key in the regulation of the gut-associated immune response. Here, we applied a multi-omics approach to investigate the molecular mechanisms that drive M cell differentiation in mouse small intestinal organoids. We generated a comprehensive profile of chromatin accessibility changes and transcription factor dynamics during in vitro M cell differentiation, allowing us to uncover numerous cell type-specific regulatory elements and associated transcription factors. By using single-cell RNA sequencing, we identified an enterocyte and M cell precursor population. We used our newly developed computational tool SCEPIA to link precursor cell-specific gene expression to transcription factor motif activity in cis-regulatory elements, uncovering high expression of and motif activity for the transcription factor ONECUT2. Subsequent in vitro and in vivo perturbation experiments revealed that ONECUT2 acts downstream of the RANK/RANKL signalling axis to support enterocyte differentiation, thereby restricting M cell lineage specification. This study sheds new light on the mechanism regulating cell fate balance in the PP, and it provides a powerful blueprint for investigation of cell fate switches in the intestinal epithelium.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors wish it to be known that, in their opinion, the second and third authors should be regarded as Joint Second Authors.
ISSN:	0305-1048 1362-4962
DOI:	10.1093/nar/gkac1236