A cytokine to remember me by

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Science Immunology  04 Dec 2020:
Vol. 5, Issue 54, eabf8871
DOI: 10.1126/sciimmunol.abf8871


Cohesin restrains cytokine-induced transcriptional memory.

Mammalian cells undergo transient gene activation in response to acute immune stimuli. Immune activation can also have long-lasting effects on gene regulation, even after the initial stimulus has been removed and transcription has returned to basal levels. This process, often termed trained immunity, can lead to a heightened response when cells are exposed to a second pulse of the same stimulus. Although this phenomenon is well documented in innate immune cells, underlying regulatory mechanisms are poorly understood. Siwek et al. aimed to define the duration, nature, and mechanisms that regulate cytokine-induced trained immunity in cancer cells. They primed HeLa cells with interferon-gamma (IFNγ) and then identified genes that underwent strong re-induction after a wash-out period. The genes that exhibited the strongest re-induction by IFNγ belonged to two specific loci, which included clusters of guanylate binding protein (GPB) and MHC class II genes. The authors characterized the priming and reinduction of GBP5, which promotes the activation of the NLRP3 inflammasome. Remarkably, GBP5 protein expression could be strongly re-induced up to 14 days (and numerous cell divisions) after initial priming, suggesting a mitotically heritable mechanism of epigenetic regulation. This memory was not dependent on ongoing transcription of GBP5 during the wash-out period and showed only modest correlations with local histone modifications. The authors evaluated the role of genome topology as a potential epigenetic mechanism of IFNγ-induced transcriptional memory of the GBP locus. They used an auxin-inducible degron system to enable global depletion of cohesin, a protein involved in the maintenance of genome topology, prior to IFNγ priming. Interestingly, global depletion of cohesin heightened the IFNγ-reinduction of GBP family and other clustered genes, suggesting that cohesin restrains trained immunity responses at these loci. They also recapitulated the reinduction phenotype for GBP genes by selective CRISPR/Cas9-mediated deletion of individual cohesion binding sites. Taken together, the authors’ findings indicate that cohesin binding restrains cytokine-induced transcriptional memory responses, including at gene clusters associated with fundamental immune regulatory processes. These studies provide a foundation for future study of the mechanistic underpinnings of trained immunity in cancer, host defense, and autoimmunity and further understanding of the specific roles of long-range chromatin interactions in mediating these processes.

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