Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level

Abstract

To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.

Decoding the dynamics of multilayered stochastic antiviral IFN-I responses

“…In addition to stochastic expression, epigenetic promoter regulation can create multigenerational cell states. For example, epigenetic regulation at one of the TLR promoters showed the predisposition of a subpopulation of human epithelial cells to respond to pathogen-associated molecular patterns (PAMPs) [92]. Lineage tracing coupled with modeling revealed that multiple gene modules, including those important for IFN-I signaling, were expressed only in small fractions of the total cell population, implying that the corresponding epigenetic signatures might predict which cells would become responders, and which ones would not [92].…”

“…For example, epigenetic regulation at one of the TLR promoters showed the predisposition of a subpopulation of human epithelial cells to respond to pathogen-associated molecular patterns (PAMPs) [92]. Lineage tracing coupled with modeling revealed that multiple gene modules, including those important for IFN-I signaling, were expressed only in small fractions of the total cell population, implying that the corresponding epigenetic signatures might predict which cells would become responders, and which ones would not [92]. Of note, the expression of these gene modules was transiently heritable, while studies in vitro showed that, in most cases, these modules were transcriptionally silenced after several generations, suggesting a complicated underlying mechanism of determining cell fate [92].…”

“…Lineage tracing coupled with modeling revealed that multiple gene modules, including those important for IFN-I signaling, were expressed only in small fractions of the total cell population, implying that the corresponding epigenetic signatures might predict which cells would become responders, and which ones would not [92]. Of note, the expression of these gene modules was transiently heritable, while studies in vitro showed that, in most cases, these modules were transcriptionally silenced after several generations, suggesting a complicated underlying mechanism of determining cell fate [92]. Along these lines, in mouse embryonic stem cells and human melanoma cells, for example, several new modeling approaches are using cell fates at the end of a cellular lineage tree to determine whether single-cell responses are purely random or a deterministic function of an underlying heritable state [57,[93][94][95].…”

Emerging roles for endogenous retroviruses in immune epigenetic regulation*

“…Beyond this regulation of intrinsic transcriptional noise, ERVs are also known to exhibit high epigenetic variability, 152,153 which may contribute to a higher order patterns of variability, such as the bimodal responsiveness of single cells to interferon signaling or differences across individuals. Like the lower order intrinsic noise that smooths signal responses through temporal variability, variability in interferon responsiveness is also thought to be functional, allowing for a flexible and tunable immune response 154 . The balance of the immune response between restraint and proper activity is crucial to organismal health and difficult to achieve through a global all‐or‐nothing signal.…”

Moment-Based Estimation of State-Switching Rates in Cell Populations

“…Recent developments in experimental technology, such as single-cell RNA-seq (scRNA-seq) have made it feasible to study the transcriptomic profiles of individual cells, yielding new insights about cellular heterogeneity at the single-cell level [15]. Heterogeneity in cell populations is known to play a role in many biological contexts, including drug response in cancer [16]- [18], latency in HIV cells [19], [20], immune response in epithelial tissue [21], determination of cell fate in genetically identical populations [22]- [31], and "bet-hedging" responses to environmental stresses in bacteria [32], [33]. For more information, an excellent review of the study of cellular heterogeneity can be found in the Altschuler and Wu (2010) paper "Cellular Heterogeneity: When Do Differences Make a Difference?"…”