Oct4 mediated inhibition of Lsd1 activity promotes the active and primed state of pluripotency enhancers

Enhancer reactivation and pluripotency gene (PpG) expression were recently shown to induce stemness and enhance tumorigenicity in cancer stem cells. Silencing of PpG enhancers during embryonic stem cell differentiation involves changes in chromatin state, facilitated by the activity of Lsd1/Mi2-NuRD-Dnmt3a complex. In this study, we observed a widespread retention of H3K4me1 at PpG enhancers and partial repression of PpGs in F9 embryonal carcinoma cells (ECCs) post differentiation. Absence of H3K4me1 demethylation could not be rescued by Lsd1 overexpression. Based on the observation that H3K4me1 demethylation is accompanied by strong Oct4 repression in P19 ECCs, we tested if Lsd1-Oct4 interaction modulates Lsd1 activity. Our data show a dose dependent inhibition of Lsd1 by Oct4 in vitro and retention of H3K4me1 at PpG enhancers post differentiation in Oct4 overexpressing P19 ECCs. These data reinforce that Lsd1-Oct4 interaction in cancer stem cells could establish a primed enhancer state, which is susceptible to reactivation.