Single-cell nucleosome mapping reveals the molecular basis of gene expression heterogeneity

Significance Nucleosomes limit access to DNA, which antagonizes gene expression and prevents recruitment of transcription factors that cannot bind DNA wrapped around the histone octamer. Numerous studies using large cell populations determined that active genes promoters tend to be nucleosome-depleted. We developed a method to examine nucleosome positioning in single cells and revealed significant heterogeneity of nucleosome configurations within a population. In an inactive gene loaded with nucleosomes, a small subpopulation of nucleosome-depleted cells exists that were engaged in transcription. Single-cell mapping revealed that even in apparently nucleosome-free regions, some cells were occupied by nucleosomes. These data reveal an underlying complexity of nucleosome positioning and its role in regulating gene expression.