Lapointe-Roberge, V. | bioRxiv Science

bioRxiv2026

Chromatin compartments define distinct modes of action and biological roles of the pioneer Pax7

Pioneer transcription factors direct cell differentiation by remodeling closed chromatin to deploy new enhancers. It remains unclear how the chromatin context shapes their action. During pituitary development, the pioneer PAX7 opens thousands of enhancers and specifies the melanotrope cell fate. We report that PAX7 acts in both the A (active) and B (inactive) genomic compartments, engaging two distinct closed states: H1-enriched chromatin in A, and H3K9me2- and lamin-rich chromatin in B. Whereas A-compartment enhancers open in a single, cell-division-independent step, B-compartment opening requires cell division and triggers domain-wide lamin dissociation coupled with B-to-A compartment shift. The two modes involve distinct biological outputs: A-compartment action modulates broadly expressed genes, whereas B-compartment action drives de novo expression of cell-type-specific developmental genes central to melanotrope identity.

genomics↗

bioRxiv2022

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

Pioneer 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 enable the pioneer Pax7 with its unique abilities. Chromatin condensation exerted by linker histone H1 is the first constraint on Pax7 recruitment, and this establishes the initial speed of chromatin remodelling. The first step of pioneer action involves recruitment of the KDM1A (LSD1) H3K9me2 demethylase for removal of this repressive mark, as well as recruitment of the MLL complex for deposition of the activating H3K4me1 mark. Further progression of pioneer action requires passage through cell division, and this involves dissociation of pioneer targets from perinuclear lamin B. 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 prior work that showed a dependence on cell division for establishment of new cell fates.

molecular biology↗