Remembering foods and foes: emerging principles of transcriptional memory.

Transcriptional memory is characterized by a primed cellular state, induced by an external stimulus that results in an altered expression of primed genes upon re-exposure to the inducing signal. Intriguingly, the primed state is heritably maintained across somatic cell divisions even after the initial stimulus and target gene transcription cease. This phenomenon is widely observed across various organisms and appears to enable cells to retain a memory of external signals, thereby adapting to environmental changes. Signals range from nutrient supplies (food) to a variety of stress signals, including exposure to pathogens (foes), leading to long-term memory such as in the case of trained immunity in plants and mammals. Here, we review these priming phenomena and our current understanding of transcriptional memory. We consider different mechanistic models for how memory can work and discuss existing evidence for potential carriers of memory. Key molecular signatures include: the poising of RNA polymerase II machinery, maintenance of histone marks, as well as alterations in nuclear positioning and long-range chromatin interactions. Finally, we discuss the potential adaptive roles of transcriptional memory in the organismal response to its environment from nutrient sensing to trained immunity.

Activation of Clustered IFNγ Target Genes Drives Cohesin-Controlled Transcriptional Memory.

Cytokine activation of cells induces gene networks involved in inflammation and immunity. Transient gene activation can have a lasting effect even in the absence of ongoing transcription, known as long-term transcriptional memory. Here we explore the nature of the establishment and maintenance of interferon γ (IFNγ)-induced priming of human cells. We find that, although ongoing transcription and local chromatin signatures are short-lived, the IFNγ-primed state stably propagates through at least 14 cell division cycles. Single-cell analysis reveals that memory is manifested by an increased probability of primed cells to engage in target gene expression, correlating with the strength of initial gene activation. Further, we find that strongly memorized genes tend to reside in genomic clusters and that long-term memory of these genes is locally restricted by cohesin. We define the duration, stochastic nature, and molecular mechanisms of IFNγ-induced transcriptional memory, relevant to understanding enhanced innate immune signaling.