BMB Section Seminar: "Impact of CDX2 regulation on intestinal phenotype by precise integration of inducible transcriptional elements"
Dr. Rita Pinto
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Copenhagen Center for Glycomics, Faculty of Health Sciences, University of Copenhagen
* Current address: Falnes lab, Section for Biochemistry and Molecular Biology, Department of Biosciences, UiO
The combined use of genome editing tools and last generation Tet-On systems allows the generation of models where gene expression can be tightly controlled. We established one of such models, based on precise integration of inducible transcriptional elements (PrIITE), for controlled induction of the intestine-specific CDX2 homeobox transcription factor under a CDX2 knock-out background ("on/off" system).
PrIITE cells generated by this approach were relevant to identify, by transcriptomic profiling, novel CDX2 downstream effector genes, as well as to understand CDX2 role in cell differentiation/dedifferentiation. CDX2 abrogation per se had an impact on the differentiation status of intestinal cells, with loss of polarity in 3D cultures, decreased expression of well-established intestinal markers (LGR5, OLFM4 and BMI1), and concomitant increased expression of the pluripotency factor SOX2. A balance between CDX2 and SOX2 expression is known to be determinant for cell fate specification during embryogenesis, and therefore, the increased SOX2 expression observed in CDX2 knock-out cells, together with the acquisition of an aggressive migratory phenotype and higher resistance to cancer therapy, might indicate a return to a “primitive” state and towards a “stem-like” phenotype.
The understanding of the CDX2 regulatory network using the PrIITE model may provide insight into the mechanisms of normal intestinal development and differentiation, as well as disease processes, namely cancer.
Rita Pinto (Photo: private)