PARP-1 Regulates Chromatin Structure and Transcription through a KDM5B-Dependent Pathway

PARP-1 is an abundant nuclear enzyme that regulates gene expression, although the underlying mechanisms are unclear. We examined the interplay between PARP-1, histone 3 lysine 4 trimethylation (H3K4me3), and linker histone H1 in the chromatin-dependent control of transcription. We show that PARP-1 is required for a series of molecular outcomes at the promoters of PARP-1-regulated genes, leading to a permissive chromatin environment that allows loading of the RNA Pol II machinery. PARP-1 does so by (1) preventing demethylation of H3K4me3 through the PARylation, inhibition, and exclusion of the histone demethylase KDM5B; and (2) promoting the exclusion of H1 and the opening of promoter chromatin. Upon depletion of PARP-1, these outcomes do not occur efficiently. Interestingly, cellular signaling pathways can use the regulated depletion of PARP-1 to modulate these chromatin-related molecular outcomes. Collectively, our results help to elucidate the roles of PARP-1 in the regulation of chromatin structure and transcription. [Display omitted] ► PARP-1 prevents H3K4me3 demethylation by PARylating, inhibiting, and excluding KDM5B ► PARP-1 and H3K4me3 block H1 binding and increase accessibility of promoter chromatin ► PARP-1-dependent chromatin opening allows loading of the RNA Pol II machinery ► Signaling pathways can deplete PARP-1 from promoters to control gene expression