Abstract
Phenotypically identical mammalian cells often display considerable variability in transcript levels of individual genes. How transcriptional activity propagates in cell lineages, and how this varies across genes is poorly understood. Here we combine live-cell imaging of short-lived transcriptional reporters in mouse embryonic stem cells with mathematical modelling to quantify the propagation of transcriptional activity over time and across cell generations in phenotypically homogenous cells. In sister cells we find mean transcriptional activity to be strongly correlated and transcriptional dynamics tend to be synchronous; both features control how quickly transcriptional levels in sister cells diverge in a gene-specific manner. Moreover, mean transcriptional activity is transmitted from mother to daughter cells, leading to multi-generational transcriptional memory and causing inter-family heterogeneity in gene expression.
Highlights
Identical mammalian cells often display considerable variability in transcript levels of individual genes
In mouse embryonic stem cells exhibiting reversible phenotypic transitions between naïve and primed states, it was found that transitions between different NANOG protein levels can exceed one generation, and after sorting for low NANOG levels there is a subpopulation without NANOG onset for 70 h, presumably as a consequence of these transitions[18]
We find that genes differ broadly in the dynamics of their transcriptional fluctuations at both short and long time-scales, which results in large differences in the propagation of transcriptional activity
Summary
Identical mammalian cells often display considerable variability in transcript levels of individual genes. Gene expression fluctuations can be caused by diverse sources, such as intrinsic noise resulting from the randomness in biochemical processes controlling gene expression, as well as extrinsic variability caused by differences in cellular parameters[7], such as size[8,9], mitochondrial content[10,11], cell cycle stage[8,12,13,14], differences in cellular microenvironment[11,15,16], or transitions between different phenotypic states[17,18] These diverse sources of variability are linked with distinct time scales. The relatedness of transcriptional activity in sibling cells and its transmission to daughter cells both structure gene expression fluctuations across lineages of phenotypically homogenous cells
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