GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers

Abstract

Summary: KDM1A-mediated H3K4 demethylation is a well-established mechanism underlying transcriptional gene repression, but its role in gene activation is less clear. Here, we report a critical function and mechanism of action of KDM1A in glucocorticoid receptor (GR)-mediated gene transcription. Biochemical purification of the nuclear GR complex revealed KDM1A as an integral component. In cell-free assays, GR modulates KDM1A-catalyzed H3K4 progressive demethylation by limiting the loss of H3K4me1. Similarly, in cells, KDM1A binds to most GR binding sites in the genome, where it removes preprogrammed H3K4me2 but leaves H3K4me1 untouched. Blocking KDM1A catalytic activity prevents H3K4me2 removal, severely impairs GR binding to chromatin, and dysregulates GR-targeted genes. Taken together, these data suggest KDM1A-mediated H3K4me2 demethylation at GRBSs promotes GR binding and plays an important role in glucocorticoid-induced gene transcription, broadening the mechanisms that contribute to nuclear receptor-mediated gene activation. : Clark et al. dissected the interplay of glucocorticoid receptor (GR) and KDM1A in glucocorticoid-mediated gene regulation. GR recruits KDM1A, which consequently removes preprogrammed H3K4me2 and stabilizes GR-chromatin interaction. KDM1A demethylation of H3K4me2 at GR-targeted enhancers is important for GC-mediated gene transcription, offering a molecular mechanism for H3K4me2 demethylation in gene activation. Keywords: glucocorticoid, KDM1A, LSD1, enhancer, H3K4me2, H3K27ac, preprogramming, nuclear receptor, dexamethasone, histone demethylase