The pluripotency transcription factor Oct4 represses heme oxygenase 1 gene in embryonic stem cells

PETRONE MV, TORO AR, VÁZQUEZ ECHEGARAY C, FRANCIA MG, OSES CM, VERNERI P, LEVI V, VÁZQUEZ E, GUBERMAN AS

Congreso; SAIC 2020; 2020

Several mechanisms ensure genomic stability avoiding the propa-gation of 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-renew-al and 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 dif-ferentiation processes, making its role in such different processesan enigma. In these contexts, the modulation of its expression re-mained unexplored. The purpose of this work was to study HO-1gene regulation in ES cells. In this work we found that HO-1 is ex-pressed in 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 plurip-otency transcription 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 experi-ments, 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 pro-vide further evidence to the connection between pluripotency andredox homeostasis and could contribute to unveil HO-1 functions.