Abstract
Genome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how coordination of ANP32E and H2A.Z contributes to genome-wide chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that ANP32E antagonizes H2A.Z accumulation to restrict chromatin accessibility genome-wide. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through subtle refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.
Highlights
Genome-wide chromatin state underlies gene expression potential and cellular function
To begin investigating our hypothesis that H2A.Z contributes to gene activation and chromatin accessibility, we assessed two embryonic mouse cell types, mouse embryonic stem cells and mouse embryonic fibroblasts (MEFs)
After partitioning the entire genome based on H2A.Z enrichment, we found that the highest levels of H2A.Z coincided with the highest degree of chromatin accessibility (Fig. 1c), and the most accessible regions had the highest levels of H2A.Z (Supplementary Fig. 1b)
Summary
Genome-wide chromatin state underlies gene expression potential and cellular function. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. The degree to which these epigenetic marks regulate TF binding, how, mechanistically, this regulation occurs, and how widespread chromatin state changes impact genome-wide expression patterns are less well established. Increased nucleosome remodeling at H2A.Z sites, which has been observed in yeast and plants[5,14,15,16], might allow for better access to DNA at H2A.Z nucleosomes compared with canonical nucleosome sites It has not yet been established whether these characteristics of H2A.Z are important for mammalian TF binding
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