Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment in the gut epithelium
Anna D'Angelo,Olivier Bluteau,Miguel A. Garcia-Gonzalez,Lionel Gresh,Antonia Doyen,Serge Garbay,Sylvie Robine,Marco Pontoglio +7 more
TLDR
This study identifies new direct target genes of the Hnf1 transcription factors and shows that they play crucial roles in both defining cell fate and controlling terminal functions in the gut epithelium.Abstract:
The intestinal epithelium is a complex system characterized by massive and continuous cell renewal and differentiation. In this context, cell-type-specific transcription factors are thought to play a crucial role by modulating specific transcription networks and signalling pathways. Hnf1alpha and beta are closely related atypical homeoprotein transcription factors expressed in several epithelia, including the gut. With the use of a conditional inactivation system, we generated mice in which Hnf1b is specifically inactivated in the intestinal epithelium on a wild-type or Hnf1a(-/-) genetic background. Whereas the inactivation of Hnf1a or Hnf1b alone did not lead to any major intestinal dysfunction, the concomitant inactivation of both genes resulted in a lethal phenotype. Double-mutant animals had defective differentiation and cell fate commitment. The expression levels of markers of all the differentiated cell types, both enterocytes and secretory cells, were affected. In addition, the number of goblet cells was increased, whereas mature Paneth cells were missing. At the molecular level, we show that Hnf1alpha and beta act upstream of the Notch pathway controlling directly the expression of two crucial components: Jag1 and Atoh1. We demonstrate that the double-mutant mice present with a defect in intestinal water absorption and that Hnf1alpha and beta directly control the expression of Slc26a3, a gene whose mutations are associated with chloride diarrhoea in human patients. Our study identifies new direct target genes of the Hnf1 transcription factors and shows that they play crucial roles in both defining cell fate and controlling terminal functions in the gut epithelium.read more
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Journal ArticleDOI
Intestinal development and differentiation
TL;DR: An overview of intestinal development and cellular differentiation of the intestinal epithelium is presented, including endoderm and gut tube formation in early embryogenesis, villus morphogenesis, and crypt formation.
Journal ArticleDOI
The SLC26 gene family of anion transporters and channels.
TL;DR: The phylogenetically ancient SLC26 gene family encodes multifunctional anion exchangers and anion channels transporting a broad range of substrates, including Cl(-), HCO3(-), sulfate, oxalate, I(-), and formate, and appear to be homo-oligomeric.
Journal ArticleDOI
Differentiation-Specific Histone Modifications Reveal Dynamic Chromatin Interactions and Partners for the Intestinal Transcription Factor CDX2
Michael P. Verzi,Hyunjin Shin,Housheng Hansen He,Rita Sulahian,Rita Sulahian,Clifford A. Meyer,Robert K. Montgomery,Robert K. Montgomery,James C. Fleet,Myles Brown,Myles Brown,X. Shirley Liu,Ramesh A. Shivdasani,Ramesh A. Shivdasani +13 more
TL;DR: Dynamic CDX2 occupancy corresponds with condition-specific gene expression and to differential co-occupancy with other tissue-restricted transcription factors, such as GATA6 and HNF4A, and reveals dynamic, context-specific functions and mechanisms of a prominent transcriptional regulator within a cell lineage.
Journal ArticleDOI
DNA methylation is required for the control of stem cell differentiation in the small intestine
Karyn L. Sheaffer,Rinho Kim,Reina Aoki,Ellen N. Elliott,Jonathan Schug,Lukas Burger,Lukas Burger,Dirk Schübeler,Dirk Schübeler,Klaus H. Kaestner +9 more
TL;DR: Determination of the base-resolution DNA methylome in intestinal stem cells and their differentiated descendants shows that DNA methylation is dynamic at enhancers, which are often associated with genes important for both stem cell maintenance and differentiation.
Journal ArticleDOI
Identification of senescent cell surface targetable protein DPP4.
Kyoung Mi Kim,Ji Heon Noh,Monica Bodogai,Jennifer L. Martindale,Xiaoling Yang,Fred E. Indig,Sandip K. Basu,Kei Ohnuma,Chikao Morimoto,Peter F. Johnson,Arya Biragyn,Kotb Abdelmohsen,Myriam Gorospe +12 more
TL;DR: Mass spectrometry analysis revealed that DPP4 was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts, which allowed flow cytometry-mediated isolation of Senescent cells using anti-DPP4 antibodies.
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