STAT1 is required to establish but not maintain interferon‐γ‐induced transcriptional memory.

Exposure of human cells to interferon‐γ (IFNγ) results in a mitotically heritable yet reversible state called long‐term transcriptional memory. We previously identified the clustered GBP genes as strongly primed by IFNγ. Here, we discovered that in primed cells, both interferon‐responsive transcription factors STAT1 and IRF1 target chromatin with accelerated kinetics upon re‐exposure to IFNγ, specifically at promotors of primed genes. Priming does not alter the degree of IFNγ‐induced STAT1 activation or nuclear import, indicating that memory does not alter upstream JAK–STAT signaling. We found STAT1 to be critical to establish transcriptional memory but in a manner that is independent of mere transcription activation. Interestingly, while Serine 727 phosphorylation of STAT1 was maintained during the primed state, STAT1 is not required for the heritability of GBP gene memory. Our results suggest that the memory of interferon exposure constitutes a STAT1‐mediated, heritable state that is established during priming. This renders GBP genes poised for subsequent STAT1 and IRF1 binding and accelerated gene activation upon a secondary interferon exposure. Synopsis: Gene activation by interferon‐γ results in mitotically heritable priming of clustered GBP genes. This study shows target gene transcription is not sufficient to induce memory but relies on STAT1‐dependent gene activation. Once primed, memory is maintained in the absence of STAT1 function. Transcription of memorized GBP genes is not sufficient to induce the primed state.Interferon‐gamma induction results in accelerated STAT1 and IRF1 recruitment in primed cells.STAT1 is essential to establish the primed state but dispensable for the memory of interferon‐γ exposure.Priming does not alter the rate of JAK–STAT signaling upon reencounter of interferon‐γ.STAT1 S727 phosphorylation is maintained during the primed state and has a role in memory. [ABSTRACT FROM AUTHOR]