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Researchers investigated how mammalian cells respond to transcription factor signals in an inducible expression system and found that while populations show gradual, dose-dependent responses, individual cells exhibit all-or-none behavior. This switch-like response is not due to random transcriptional bursting or temporary bistability, but rather to stable, long-lasting differences in chromatin structure that create variable activation thresholds across cells. These chromatin-encoded variations persist over time and explain why gene expression appears bimodal across cell populations despite graded input signals.
Why it matters
Understanding the mechanistic basis of cell-to-cell variability in gene expression is crucial for designing predictable synthetic biology systems and gene therapies in mammalian cells. The finding that chromatin state creates stable activation thresholds also has implications for understanding how cells make consistent developmental decisions and respond to signaling molecules.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Quantitatively relating transcription factor (TF) input to gene expression output is central to understanding mammalian gene regulation and essential for designing predictable synthetic expression systems. However, even minimal synthetic systems often exhibit unexplained behaviors. In a widely used inducible mammalian expression system, we show that transcriptional responses appear graded and sigmoidal at the population level but are largely all-or-none at the single-cell level. By combining single-cell sorting and single-molecule footprinting with mathematical modeling of transcriptional regulation, we found that this behavior is not caused by bursty transcription or bistability, but by long-lived, chromatin-encoded variability in TF occupancy and activation strength. This variability produced a range of activation thresholds in switch-like single-cell responses that were stable over time, resulting in bimodal gene expression across the population. These results advance our basic understanding of how TFs interact with chromatin to modulate quantitative features of single-cell and population level transcriptional responses.
Source: Stable epigenetic states set single-cell activation thresholds in mammalian expression systems