Gene networks with transcriptional bursting recapitulate rare transient coordinated expression states in cancer

Abstract

Non-genetic transcriptional variability at the single-cell level is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of melanoma cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes. Importantly, these rare cells are able to survive drug treatment and develop resistance. How might these extremely rare states arise and disappear within the population? It is unclear whether the canonical stochastic models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified molecular mechanisms. Here we use mathematical modeling to show that a minimal network comprising of transcriptional bursting and interactions between genes can give rise to rare coordinated high states. We next show that although these states occur across networks of different sizes, they depend strongly on three (out of seven) model parameters and require network connectivity to be ≤ 6. Interestingly, we find that while entry into the rare coordinated high state is initiated by a long transcriptional burst that also triggers entry of other genes, the exit from it occurs through the independent inactivation of individual genes. Finally, our model predicts that increased network connectivity can lead to transcriptionally stable states, which we verify using network inference analysis of experimental data. In sum, we demonstrate that established principles of gene regulation are sufficient to describe this new class of rare cell variability and argue for its general existence in other biological contexts.

Retrospective identification of intrinsic factors that mark pluripotency potential in rare somatic cells

“…In the case of cancer therapy resistance, we found evidence for multiple axes of variability (Dardani et al, 2022;Emert et al, 2021). Another question is whether primed cell states form a continuum, or if they consist of discrete metastable states that cells can fluctuate between (Chang et al, 2008;Mojtahedi et al, 2016;Schuh et al, 2020). It is difficult to answer this question with current approaches.…”