LSD1-ERRα complex requires NRF1 to positively regulate transcription and cell invasion.

Lysine-specific demethylase 1 (LSD1) exerts dual effects on histone H3, promoting transcriptional repression via Lys4 (H3K4) demethylation or transcriptional activation through Lys9 (H3K9) demethylation. These activities are often exerted at transcriptional start sites (TSSs) and depend on the type of enhancer-bound transcription factor (TFs) with which LSD1 interacts. In particular, the Estrogen-Receptor Related α (ERRα) TF interacts with LSD1 and switches its activities toward H3K9 demethylation, resulting in transcriptional activation of a set of common target genes. However, how are the LSD1-TF and, in particular LSD1-ERRα, complexes determined to act at TSSs is not understood. Here we show that promoter-bound nuclear respiratory factor 1 (NRF1), but not ERRα, is essential to LSD1 recruitment at the TSSs of positive LSD1-ERRα targets. In contrast to ERRα, NRF1 does not impact on the nature of LSD1 enzymatic activity. We propose a three factor model, in which the LSD1 histone modifier requires a TSS tethering factor (NRF1) as well as an activity inducer (ERRα) to transcriptionally activate common targets. The relevance of this common network is illustrated by functional data, showing that all three factors are required for cell invasion in an MMP1 (Matrix MetalloProtease 1)-dependent manner, the expression of which is regulated by NRF1/LSD1/ERRα-mediated H3K9me2 demethylation.