New publication in "Nucleic Acids Research"
In this publication, the group of Philipp Rathert developed a hypothesis free approach to investigate coregulators of the histone demethylase LSD1. To this end they established a novel tractable fluorescent reporter system to monitor LSD1 activity in living cells. Combining this reporter system with a state-of-the-art multiplexed RNAi screen allowed to comprehensively characterize functional coregulators of LSD1 and to identify the DEAD-box helicase 19A (DDX19A) as a novel coregulator of LSD1. Subsequent analysis of the biological function provided evidence for a novel transcriptional regulatory cascade where LSD1 is initially suppressed at target gene promoters by DNA:RNA hybrids, so called R-loops. Resolution of R-loops by Ddx19A is a first and essential step for LSD1 to become catalytically active. H3K4 demethylation and R-loop removal activate PRC2, which then introduces H3K27me3 methylation leading to stronger Ddx19A recruitment and/or activity. Finally, the recruitment of DDX19A leads to the removal of R-loops at active promoters inducing a strong transcriptional shutdown.