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

Abstract

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.

HOTAIR lncRNA promotes epithelial–mesenchymal transition by redistributing LSD1 at regulatory chromatin regions

“…Such low overlap may point to significant differences between steady-state transcriptome and H3K27ac status reflecting differences between chromatin modifications associated with transcriptional activity of the locus and total RNA levels at the equilibrium between RNA synthesis and stability. Several studies propose LSD1 as a factor involved in regulation of promoter activities (Ferrari-Amorotti et al, 2013;Ambrosio et al, 2017;Carnesecchi et al, 2017;Zhang et al, 2018). To address how LSD1 occupancy of promoters is affected in the presence of HOTAIR, we performed CUT&RUN profiling of LSD1 in our system.…”

Nuclear Respiratory Factor 1 Promotes The Growth of Liver Hepatocellular Carcinoma Cells Via E2F1 Transcriptional Activation

“…It has been suggested that NRF1 is essential for lysine-speci c demethylase 1 (LSD1) histone modi cation. The complex of NRF1, LSD1 and oestrogen-receptor related α (ERRα) is required for cell invasion in a matrix metalloprotease 1 (MMP1)dependent manner [34]. NRF1 also forms an activator complex with egl-9 family hypoxia inducible factor 2 (EglN2) to promote ferridoxin reductase (FDXR) transcription activation.…”

shRNA-interfering LSD1 inhibits proliferation and invasion of gastric cancer cells via VEGF-C/PI3K/AKT signaling pathway

“…Studies have shown that LSD1 can demethylate H3K4mel/2 and H3K9mel/2, thereby regulating downstream gene transcription. LSDl can remove methylation of the tumor suppressor protein p53 K370, inhibit p53 activity, and inhibit p53 target gene expression [11][12][13][14] .…”