Pioneer factor Pax7 initiates two-step cell-cycle dependent chromatin opening

Abstract

SummaryPioneer transcription factors direct cell differentiation by deploying new enhancer repertoires through their unique ability to target and initiate remodelling of closed chromatin. The initial steps of their action remain undefined although pioneers were shown to interact with nucleosomal target DNA and with some chromatin remodelling complexes. We now define the sequence of events that provide pioneers with their unique abilities. Chromatin condensation exerted by linker histone H1 is the first constraint on pioneer recruitment, and this establishes the initial speed of chromatin remodelling. The first step of pioneer action involves recruitment of the LSD1 H3K9me2 demethylase for removal of this repressive mark, as well as recruitment of the MLL complex for deposition of the H3K4me1 mark. Further progression of pioneer action requires passage through cell division, and this involves dissociation of pioneer targets from perinuclear lamins. Only then, the SWI/SNF remodeling complex and the coactivator p300 are recruited, leading to nucleosome displacement and enhancer activation. Thus, the unique features of pioneer actions are those occurring in the lamin-associated compartment of the nucleus. This model is consistent with much prior work that showed a dependence on cell division for establishment of new cell fates.