A study published in Nature (2015) introduces a method called single-cell ATAC-seq (scATAC-seq) to map DNA accessibility in individual cells. This technique allows for the identification of regulatory variation across cell types and provides insights into the mechanisms underlying cell-to-cell differences in gene regulation. The study reveals that accessibility variance is systematically associated with specific trans-factors and cis-elements, and that combinations of trans-factors can induce or suppress variability. The research also identifies sets of trans-factors associated with cell-type specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signaling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome topological domains, linking single-cell accessibility variation to three-dimensional genome organization. The study demonstrates that single-cell analysis of DNA accessibility provides new insight into cellular variation of the "regulome." The findings suggest that trans-factors promote cell-type specific chromatin accessibility variation genome-wide. The study also shows that variability can be experimentally modulated and that variability is not solely dependent on the cell-cycle. The results highlight the importance of trans-factors in driving regulatory variation and suggest that differences in the global levels of trans-factor variability across cell lines may contribute to cellular heterogeneity. The study also reveals that chromatin accessibility variation is highly correlated with previously reported chromosome compartments, opening the possibility that this component of epigenomic noise has its roots in higher-order chromatin organization. Overall, the study provides exciting new hypotheses of regulatory mechanisms that give rise to single-cell heterogeneity.A study published in Nature (2015) introduces a method called single-cell ATAC-seq (scATAC-seq) to map DNA accessibility in individual cells. This technique allows for the identification of regulatory variation across cell types and provides insights into the mechanisms underlying cell-to-cell differences in gene regulation. The study reveals that accessibility variance is systematically associated with specific trans-factors and cis-elements, and that combinations of trans-factors can induce or suppress variability. The research also identifies sets of trans-factors associated with cell-type specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signaling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome topological domains, linking single-cell accessibility variation to three-dimensional genome organization. The study demonstrates that single-cell analysis of DNA accessibility provides new insight into cellular variation of the "regulome." The findings suggest that trans-factors promote cell-type specific chromatin accessibility variation genome-wide. The study also shows that variability can be experimentally modulated and that variability is not solely dependent on the cell-cycle. The results highlight the importance of trans-factors in driving regulatory variation and suggest that differences in the global levels of trans-factor variability across cell lines may contribute to cellular heterogeneity. The study also reveals that chromatin accessibility variation is highly correlated with previously reported chromosome compartments, opening the possibility that this component of epigenomic noise has its roots in higher-order chromatin organization. Overall, the study provides exciting new hypotheses of regulatory mechanisms that give rise to single-cell heterogeneity.