Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

A. Treveil, P. Sudhakar, Z. J. Matthews, T. Wrzesiński, E. J. Jones, J. Brooks, M. Ölbei, I. Hautefort, L. J. Hall, S. R. Carding, U. Mayer, P. P. Powell, T. Wileman, F. Di Palma, W. Haerty, T. Korcsmáros*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


The epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3D in vitro cultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long non-coding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn's disease or ulcerative colitis.

Original languageEnglish
Pages (from-to)39-58
Number of pages20
JournalMolecular Omics
Issue number1
Publication statusPublished - Feb 2020

Bibliographical note

Funding Information:
This work was supported by a fellowship to TK in computational biology at the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute (Norwich, UK), and strategically supported by the Biotechnological and Biosciences Research Council, UK grants (BB/J004529/1, BB/P016774/1 and BB/CSP17270/1). SRC, LH, TWi and TK were also funded by a BBSRC ISP grant for Gut Microbes and Health BB/R012490/1 and its constituent project(s), BBS/E/F/000PR10353 and BBS/E/ F/000PR10355. ZM was supported by a PhD studentship from Norwich Medical School. PP was supported by the BBSRC grant BB/J01754X/1. AT and MO were supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership (grant BB/M011216/1). TWr and WH were supported by an MRC award (MR/P026028/1). Next-generation sequencing and library construction was delivered via the BBSRC National Capability in Genomics and Single Cell (BB/CCG1720/1) at Earlham Institute by members of the Genomics Pipelines Group.

Publisher Copyright:
© 2020 The Royal Society of Chemistry.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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