CONICET | Buscador de Institutos y Recursos Humanos

Several mechanisms ensure genomic stability avoiding the propagationof genetic damage in embryonic stem (ES) cells, which candifferentiate into all the adult cell lineages including the germ line. Inthese cells, redox status regulates the balance between self-renewaland differentiation, making crucial oxidative stress control. Hemeoxygenase (HO) is the limiting enzyme in heme catabolism, and theinducible isoform HO-1 is known by its antioxidant and antiapoptoticfunctions. In the last years, new functions of HO-1 in the context ofpluripotency were reported. Interestingly, it is required for efficientinduced pluripotent stem cells generation and also, for specific differentiationprocesses, making its role in such different processesan enigma. In these contexts, the modulation of its expression remainedunexplored. The purpose of this work was to study HO-1gene regulation in ES cells. In this work we found that HO-1 is expressedin ES cells, localize both in nucleus and cytoplasm and isinduced during differentiation. Since in silico analysis of HO-1 genepromoter region displayed multiple putative binding sites for pluripotencytranscription factors (TFs) we analyzed whether they wereinvolved in HO-1 gene regulation by a shRNA approach. We foundthat Oct4 downregulation increased HO-1 mRNA levels in ES cells.In agreement, by analyzing available data from ChIP-seq experiments,we found that this TF binds to HO-1 promoter region in EScells. Moreover, Oct4 ectopic expression in heterologous systemsrepressed both HO-1 gene promoter reporter and endogenousHO-1 gene, further supporting that this pluripotency TF repressesHO-1 gene expression. We have previously found pluripotency TFsregulate the expression of other relevant genes involved in oxidativestress defense in ES cells. The results presented in this work providefurther evidence to the connection between pluripotency andredox homeostasis and could contribute to unveil HO-1 functions.