Molecular noise is a natural phenomenon inherent to all biological systems1,2. How stochastic processes give rise to the robust outcomes supportive of tissue homeostasis is a conundrum. Here, to quantitatively investigate this issue, we use single-molecule mRNA FISH (smFISH) on stem cells derived from hematopoietic tissue to measure the transcription dynamics of three key transcription factor (TF) genes: PU.1, Gata1 and Gata2. Our results indicate that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic TF in the majority of hematopoietic stem and progenitor cells. Moreover, by pairing smFISH to time-lapse microscopy and the analysis of pedigrees, we find that while individual stem cell clones produce offspring that are in transcriptionally related states, akin to a transcriptional priming phenomenon, the underlying transition dynamics between states are nevertheless best captured by stochastic and reversible models. As such, the outcome of a stochastic process can produce cellular behaviors that may be incorrectly inferred to have arisen from deterministic dynamics. In light of our findings, we propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, concomitant maintenance of transcriptional plasticity and stem cell robustness.

1. Justin C. Wheat (Justin.Wheat@einsteinmed.org)

1. Robert H. Singer (robert.singer@einsteinmed.org)

1. Ulrich Steidl (ulrich.steidl@einsteinmed.org )

1. …

Wheat JC, Sella Y, Willcockson MA, Skoultchi A, Bergman A, Singer RH, Steidl U. Single molecule imaging of transcription dynamics in somatic stem cells. Nature. 2020. Accepted.