Gene-Specific H1 Eviction through a Transcriptional Activator→p300→NAP1→H1 Pathway

Linker histone H1 has been correlated with transcriptional inhibition, but the mechanistic basis of the inhibition and its reversal during gene activation has remained enigmatic. We report that H1-compacted chromatin, reconstituted in vitro, blocks transcription by abrogating core histone modifications by p300 but not activator and p300 binding. Transcription from H1-bound chromatin is elicited by the H1 chaperone NAP1, which is recruited in a gene-specific manner through direct interactions with activator-bound p300 that facilitate core histone acetylation (by p300) and concomitant eviction of H1 and H2A-H2B. An analysis in B cells confirms the strong dependency on NAP1-mediated H1 eviction for induction of the silent CD40 gene and further demonstrates that H1 eviction, seeded by activator-p300-NAP1-H1 interactions, is propagated over a CCCTC-binding factor (CTCF)-demarcated region through a distinct mechanism that also involves NAP1. Our results confirm direct transcriptional inhibition by H1 and establish a gene-specific H1 eviction mechanism through an activator→p300→NAP1→H1 pathway. [Display omitted] •H1 blocks transcription in part by blocking core histone acetylation by p300•An activator-p300 and NAP1 pathway evicts H1 in a gene- and activator-specific manner•Gene activation in cells leads to a wave of H1 eviction from activator binding sites•The wave of H1 eviction ends at the nearest CTCF binding site Shimada et al. report that H1 eviction during transcription entails NAP1 recruitment by activator-bound p300, leading to histone acetylation and simultaneous removal of H1 and H2A-H2B. A B cell maturation model further demonstrates that H1 eviction is seeded by activator-p300 and NAP1 and continues in a wave to the nearest CTCF binding sites.