This study investigates the origins of cell-to-cell variations in gene expression in mammalian cells by counting individual mRNA molecules produced from a reporter gene integrated into the cell's genome. The researchers found that mRNA levels vary significantly between cells, with bursts of transcription occurring when the gene transitions from an inactive to an active state. These transitions are intrinsically random and not influenced by extrinsic factors such as transcriptional activator levels. The bursts affect the expression of entire genomic loci, and the mRNA produced by the gene encoding RNA polymerase II also exhibits similar bursts. The study developed a stochastic model of gene activation and inactivation, showing that increasing the level of transcriptional activators increases the average size of the bursts rather than their frequency. The results highlight the presence of large, intrinsically random fluctuations in gene expression and raise questions about how cells function in the face of such noise.This study investigates the origins of cell-to-cell variations in gene expression in mammalian cells by counting individual mRNA molecules produced from a reporter gene integrated into the cell's genome. The researchers found that mRNA levels vary significantly between cells, with bursts of transcription occurring when the gene transitions from an inactive to an active state. These transitions are intrinsically random and not influenced by extrinsic factors such as transcriptional activator levels. The bursts affect the expression of entire genomic loci, and the mRNA produced by the gene encoding RNA polymerase II also exhibits similar bursts. The study developed a stochastic model of gene activation and inactivation, showing that increasing the level of transcriptional activators increases the average size of the bursts rather than their frequency. The results highlight the presence of large, intrinsically random fluctuations in gene expression and raise questions about how cells function in the face of such noise.