TY - JOUR
T1 - Integrative multi-omics analysis of intestinal organoid differentiation
AU - Lindeboom, Rik G.H.
AU - van Voorthuijsen, Lisa
AU - Oost, Koen C.
AU - Rodríguez-Colman, Maria J.
AU - Luna-Velez, Maria V.
AU - Furlan, Cristina
AU - Baraille, Floriane
AU - Jansen, Pascal W.T.C.
AU - Ribeiro, Agnès
AU - Burgering, Boudewijn M.T.
AU - Snippert, Hugo J.
AU - Vermeulen, Michiel
N1 - Funding Information:
We thank all the members of the Vermeulen laboratory for fruitful discussions. We thank F. de Sauvage (Genentech) for providing organoid cultures of Lgr5-DTR-GFP knock-in mice, Deltagen Inc., for supplying the Hnf4g+/− mice, Eva Janssen-Megens from the Radboud University for help with next-generation sequencing, and Dr. Edwin Stigter from the Medical Metabolomics Facility UMCU for performing LC-MS/MS-based metabolomics. The Vermeulen, Snippert, and Burgering laboratories are part of the Oncode Institute which is partly financed by the Dutch Cancer Society (KWF). Furthermore, work in the Vermeulen and Burgering laboratory is funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research (NWO).
Funding Information:
We thank all the members of the Vermeulen laboratory for fruitful discussions. We thank F. de Sauvage (Genentech) for providing organoid cultures of Lgr5-DTR-GFP knock-in mice, Deltagen Inc., for supplying the Hnf4g+/−mice, Eva Janssen-Megens from the Radboud University for help with next-generation sequencing, and Dr. Edwin Stigter from the Medical Metabolomics Facility UMCU for performing LC-MS/MS-based metabolomics. The Vermeulen, Snippert, and Burgering laboratories are part of the Oncode Institute which is partly financed by the Dutch Cancer Society (KWF). Furthermore, work in the Vermeulen and Burgering laboratory is funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research (NWO).
Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/6/26
Y1 - 2018/6/26
N2 - Intestinal organoids accurately recapitulate epithelial homeostasis in vivo, thereby representing a powerful in vitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi-omics framework on stem cell-enriched and stem cell-depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription-driven. Integrating absolute mRNA and protein copy numbers revealed post-transcriptional regulation of gene expression. Probing the epigenetic landscape identified a large number of cell-type-specific regulatory elements, which revealed Hnf4g as a major driver of enterocyte differentiation. In summary, by applying an integrative systems biology approach, we uncovered multiple layers of gene expression regulation, which contribute to lineage specification and plasticity of the mouse small intestinal epithelium.
AB - Intestinal organoids accurately recapitulate epithelial homeostasis in vivo, thereby representing a powerful in vitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi-omics framework on stem cell-enriched and stem cell-depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription-driven. Integrating absolute mRNA and protein copy numbers revealed post-transcriptional regulation of gene expression. Probing the epigenetic landscape identified a large number of cell-type-specific regulatory elements, which revealed Hnf4g as a major driver of enterocyte differentiation. In summary, by applying an integrative systems biology approach, we uncovered multiple layers of gene expression regulation, which contribute to lineage specification and plasticity of the mouse small intestinal epithelium.
KW - adult intestinal stem cells
KW - enterocytes
KW - Hnf4g
KW - organoids
KW - systems biology
UR - https://www.scopus.com/pages/publications/85049264663
U2 - 10.15252/msb.20188227
DO - 10.15252/msb.20188227
M3 - Article
C2 - 29945941
AN - SCOPUS:85049264663
SN - 1744-4292
VL - 14
JO - Molecular Systems Biology
JF - Molecular Systems Biology
IS - 6
M1 - e8227
ER -