Temporal signaling, population control, and information processing through chromatin-mediated gene regulation

Abstract

Chromatin regulation is a key pathway cells use to regulate gene expression in response to temporal stimuli, and is becoming widely used as a platform for synthetic biology applications. Here, we build a mathematical framework for analyzing the response of genetic circuits containing chromatin regulators to temporal signals in mammalian cell populations. Chromatin regulators can silence genes in an all-or-none fashion at the single-cell level, with individual cells stochastically transitioning between active, reversibly silent, and irreversibly silent gene states at constant rates over time. We integrate this mode of regulation with classical gene regulatory motifs, such as autoregulatory and incoherent feedforward loops, to determine the types of responses achievable with duration-dependent signaling. We demonstrate that repressive regulators without long-term epigenetic memory can filter out high frequency noise, and as part of an autoregulatory loop can precisely tune the fraction of cells in a population that expresses a gene of interest. Additionally, we find that repressive regulators with epigenetic memory can sum up and encode the total duration of their recruitment in the fraction of cells irreversibly silenced and, when included in a feed forward loop, enable perfect adaptation. Last, we use an information theoretic approach to show that all-or-none stochastic silencing can be used by populations to transmit information reliably and with high fidelity even in very simple genetic circuits. Altogether, we show that chromatin-mediated gene control enables a repertoire of complex cell population responses to temporal signals and can transmit higher information levels than previously measured in gene regulation.