Lionel Gresh

Bio: Lionel Gresh is an academic researcher from Paris Descartes University. The author has contributed to research in topics: Cellular differentiation & Cell fate determination. The author has an hindex of 1, co-authored 1 publications receiving 81 citations.

Hepatocyte nuclear factor 1α and β control terminal differentiation and cell fate commitment 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.

DNA methylation is required for the control of stem cell differentiation in the small intestine

Abstract: The mammalian intestinal epithelium has a unique organization in which crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every 3-5 d throughout adult life. Disrupted maintenance of the intricate balance of proliferation and differentiation leads to loss of epithelial integrity or barrier function or to cancer. There is a tight correlation between the epigenetic status of genes and expression changes during differentiation; however, the mechanism of how changes in DNA methylation direct gene expression and the progression from stem cells to their differentiated descendants is unclear. Using conditional gene ablation of the maintenance methyltransferase Dnmt1, we demonstrate that reducing DNA methylation causes intestinal crypt expansion in vivo. 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. We establish that the loss of DNA methylation at intestinal stem cell gene enhancers causes inappropriate gene expression and delayed differentiation.

Identification of senescent cell surface targetable protein DPP4.

Abstract: Senescent cell accumulation in aging tissues is linked to age-associated diseases and declining function, prompting efforts to eliminate them. Mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts. Importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies. Moreover, antibody-dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells. In sum, the selective expression of DPP4 on the surface of senescent cells enables their preferential elimination.