Isogenic cells in a common environment show substantial cell-to-cell variation in gene expression, often referred to as "expression noise." Here, we use multiple single-cell RNA-sequencing datasets to identify features associated with high or low expression noise in mouse embryonic stem cells. These include the core promoter architecture of a gene, with CpG island promoters and a TATA box associated with low and high noise, respectively. High noise is also associated with "conflicting" chromatin states-the absence of transcription-associated histone modifications or the presence of repressive ones in active genes. Genes regulated by pluripotency factors through super-enhancers show high and correlated expression variability, consistent with fluctuations in the pluripotent state. Together, our results provide an integrated view of how core promoters, chromatin, regulation, and pluripotency fluctuations contribute to the variability of gene expression across individual stem cells.

This work was supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Economy and Competitiveness (BFU2011-26206 and “Centro de Excelencia Severo Ochoa 2013-2017” SEV-2012-0208), the AXA Research Fund, the Bettencourt Schueller Foundation, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), FP7 project 4DCellFate (277899), and the EMBL-CRG Systems Biology Program. AF was supported by a MINECO post-doctoral grant (FPDI-2013-17783)