The miR-34/449 family of microRNAs prevents stemness and promotes differentiation

• Applicant: Dr. Muriel Lizé
• Subject Area: General Genetics and Functional Genome Biology ; Cell Biology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 250588082

Cell fate determination is an important process in biology, and a change in cell fate is often associated with pathological disorders like cancer. The miR-34/449 family of microRNAs is preferentially found in differentiated tissues and lost in undifferentiated tumor cells. This family of microRNAs has a putative role in cell fate determination through the regulation of the p53 pathway and stemness factors. Our working hypothesis is that these microRNAs represent a barrier to dedifferentiation, and therefore to the induction of pluripotency in vitro, by up-regulating the p53 pathway. This would protect tissues from uncontrolled proliferation and tumorigenesis. We further hypothesize that these microRNAs are necessary for the proper and ordered differentiation of many cell types and, therefore, for tissue homeostasis. To address those questions, we have generated a mouse strain lacking the three clustered miR-449a, b and c, which will be the basis for our studies both in animals and in cultured cells. Although the mice are viable, we found that the deletion of miR-449 enhances the efficiency of somatic cell reprogramming, when generating induced pluripotent stem cells (iPSCs). To extend our genetic approach, we are using mouse strains lacking the three miR-34s, to breed for a complete knock-out of the six members of this microRNA family. We intend to define the function of miR-34/449 in the cell s decision between differentiation and stemness by using in vitro systems of stem cell generation and ciliated differentiation. The differentiation potential of the miR-34/449 cells will be also investigated in vivo by analyzing the cell type distribution in the bronchial epithelium, and by assessing T cell differentiation in the thymus. Thereby, these studies would imply the miR-34/449 family as a novel player in differentiation and cell fate determination.

• DFG Programme: Research Grants