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

Highlights

• IFNγ induces transcriptional memory for up to 14 days in cycling cells

• Transcription during priming increases probability to reinduce

• Changes in local chromatin structure at primed genes are maintained short term

• IFNγ-induced memory in gene clusters is locally controlled by cohesin

Summary

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.