Multiple Regulators Mediate The Transcriptional Activities Of ERRalpha And Itscapacity To Promote Cell Invasion

ERRα is a nuclear receptor whose activity mainly depends on its interaction with transcription co-regulators.High levels of ERRα are found in various cancer types and correlate with poor prognosis.However,the mechanisms linking ERRα to cancer cell migration as well as the coregulators involved are unclear.In our study,we found two histone-modifying enzymes,LSD1 and SET7,acting as positive regulators of ERRα.Ⅰ.ERRα impacts the biochemical activities of the LSD1 demethylase.Activation of ERRα-LSD1 targets(identified by RNA-Seq)requires the recruitment of this complex at Transcriptional Start Sites(TSSs),which is achieved by the NRF1 transcription factor.In our study,we have shown several points: NRF1,but not ERRα,is involved in positioning LSD1 to TSS,whereas ERRα,but not NRF1,regulates LSD1 enzymatic activities towards demethylating H3K9me2.Ⅱ.A distinct group of ERRα target genes(identified by RNA-Seq)is under the control of the histone methyltransferase SET7 which mono-methylates H3K4.Appropriate recruitment of SET7 at TSSs is controlled by the ETS1 transcription factor,promoting the interaction between SET7-ERRα,leading to target gene expression.Gene Ontology analysis revealed that ERRα-LSD1 co-targets,as well as ERRα-SET7 cotargets,are enriched in terms of cell invasion.Consistently,depletion of each of these factors,as well as depletion of NRF1 or ETS1,leads to reduced cell invasion capacities as observed in transwell assays or in vivo,using xenotransplantation in the zebrafish embryo.Altogether,our results show two regulatory networks involving histone modifications induced by nuclear receptors,leading to increased cell invasion.