Activation of clustered IFNγ target genes drives cohesin-controlled transcriptional memory. Siwek et al

Cytokine activation of cells induces gene networks involved in inflammation and immunity. Transient gene activation can have a lasting impact even in the absence of ongoing transcription, known as long-term transcriptional memory. Here we explore the nature of the establishment and maintenance of IFNγ-induced priming of human cells. We find that while both 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 of enhanced innate immune signaling.

细胞因子激活细胞后，会诱导参与炎症与免疫反应的基因网络。即使在持续转录停止的情况下，瞬时基因激活仍可产生持久影响，这种现象被称为长期转录记忆。在此，我们探究了人类细胞中干扰素γ (IFNγ) 诱导的预激活状态的建立与维持机制。研究发现，尽管持续转录与局部染色质特征均为瞬时存在，但干扰素γ预激活状态可稳定传递至少14个细胞分裂周期。单细胞分析显示，记忆效应表现为预激活细胞参与靶基因表达的概率升高，且该概率与初始基因激活的强度呈正相关。此外，我们发现具有强记忆效应的基因往往位于基因组簇中，且这类基因的长期记忆效应会受到黏连蛋白 (cohesin) 的局部限制。本研究明确了干扰素γ诱导的转录记忆的持续时长、随机特性与分子机制，相关结果有助于理解增强的先天免疫信号通路。