The Pioneer Transcription Factor FoxA Maintains an Accessible Nucleosome Configuration at Enhancers for Tissue-Specific Gene Activation

Nuclear DNA wraps around core histones to form nucleosomes, which restricts the binding of transcription factors to gene regulatory sequences. Pioneer transcription factors can bind DNA sites on nucleosomes and initiate gene regulatory events, often leading to the local opening of chromatin. However, the nucleosomal configuration of open chromatin and the basis for its regulation is unclear. We combined low and high levels of micrococcal nuclease (MNase) digestion along with core histone mapping to assess the nucleosomal configuration at enhancers and promoters in mouse liver. We find that MNase-accessible nucleosomes, bound by transcription factors, are retained more at liver-specific enhancers than at promoters and ubiquitous enhancers. The pioneer factor FoxA displaces linker histone H1, thereby keeping enhancer nucleosomes accessible in chromatin and allowing other liver-specific transcription factors to bind and stimulate transcription. Thus, nucleosomes are not exclusively repressive to gene regulation when they are retained with, and exposed by, pioneer factors. [Display omitted] •Liver-specific enhancers retain accessible nucleosomes more than ubiquitous enhancers•FoxA binding displaces linker histone and keeps nucleosomes accessible•FoxA2 is enriched near the dyad axis of accessible nucleosomes with other liver TFs•FoxA-bound nucleosomes at enhancers stimulate liver gene activation Using low- and high-MNase sequencing with core histone mapping, Iwafuchi-Doi et al. reveal that tissue-specific enhancers retain accessible nucleosomes more than promoters and ubiquitous enhancers in mammalian chromatin. The pioneer factor FoxA displaces linker histone, thereby keeping nucleosomes accessible and allowing other liver-specific transcription factors to bind and stimulate gene activation.