Pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation [ChIP-seq]

Nuclear DNA is wrapped around core histones to form nucleosomes, which constrains how transcription factors bind to gene regulatory sequences. Pioneer transcription factors have the special ability to bind target DNA on nucleosomes and initiate gene regulatory events, often leading to a local opening of chromatin. Yet the nucleosomal configuration of such open chromatin and the basis for chromatin opening is unclear. Here we combine low and high levels of MNase digestion along with core histone ChIP-seq to assess the presence of nucleosomes at enhancers and promoters in mouse liver. We find that the pioneer factor FoxA displaces linker histone H1, thereby keeping enhancer nucleosomes accessible in chromatin and helping other transcription factors bind. MNase-accessible nucleosomes, bound by transcription factors, are retained substantially more at liver-specific enhancers than promoters and tissue-ubiquitous enhancers. Thus, nucleosomes are not exclusively repressive to gene regulation when they are retained with, and exposed by, pioneer factors. Overall design: This study assesses genome-wide binding of the transcription factors FoxA3, HNF4a, and CEBPb along with linker histone H1 in WT mice and in FoxAflox;Alfp-Cre mutant mice lacking both FoxA1 and FoxA2. ChIP-seq signal is adjusted by input to account for local sonication efficiency biases. All ChIPs and the input were assessed using two biological replicates in each genetic background.