KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal transition

Differential expression of genes involved in certain processes is a collaborative outcome of crosstalk between signalling molecules and epigenetic modifiers. In response to environmental stimulus, interplay between transcription factors and epigenetic modifiers together dictates the regulation of genes. MLLs and KDM5A are functionally antagonistic proteins, as one acts as a writer and the other erases the active chromatin mark, i.e., H3K4me3. KDM5A influences the process of EMT by binding to both epithelial and mesenchymal gene promoters. Through this work, we show that when bound to E-cadherin promoter, KDM5A acts as a classical repressor by demethylating H3K4me3, but on mesenchymal markers, it acts as a transcriptional activator by inhibiting the activity of HDACs and increasing H3K18ac. Further, through our chromatin immunoprecipitation experiments, we observed a co-occupancy of KDM5A with MLLs, we tested whether KDM5A might physically interact with MLLs and WDR5, and here we provide experimental evidence that KDM5A indeed interacts with MLLs and WDR5. •KDM5A interacts with MLL1/2 to regulate genes by or no H3K4me3 demethylation.•KDM5A activates mesenchymal marker genes by inhibiting HDACs activity.•KDM5A is identified and probed as a new member of COMPASS.•Interactions of KDM5A catalytic and PHD2 domains with MLL2 and WDR5 are probed.