STAT1 is required to establish but not maintain IFNγ-induced transcriptional memory

Abstract

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 signalling. 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 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.

Uncovering the Single-cell Transcriptomic Signatures and Pathogenesis of Mucosal-associated Invariant T cells during Nonalcoholic Steatohepatitis

“…Signal transducer and activator of transcription 1 (STAT1) belongs to the STAT protein family and mediates cellular responses to the Janus kinase (JAK)-signal, interferons (e.g., IFN-γ), IFN-stimulated genes (ISG) and relative modulators (e.g., KITLG/SCF, IRF-9), and the dysfunction of STAT1 commonly causes diverse immune dysregulation phenotypes [40][41][42][43]. For example, Grohmann et al put forward contribution of obesity-associated hepatic oxidative stress upon the pathogenesis of NASH in C57BL/6 mice via increasing STAT1/STAT3 signaling and inactivating the T cell protein tyrosine phosphatase (TCPTP) [32].…”

Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases

“…This transcriptional adaptation is facilitated by both ‘cis-acting’ factors such as DNA methylation or histone modifications, which may be locally inherited through the cell cycle, and by ‘trans-acting’ factors such as transcription factors that re-initiate and/or maintain the signal even in its absence 263. Not surprisingly, trained immunity is regulated by the epigenome.…”

“…This chromatin opening is facilitated by H3K4me3 marks and can be retained for a year,25 28 illustrating the importance of epigenetic mechanisms mediating cellular innate immune memory 267. This epigenetically driven long-term transcriptional memory is observed on exposure to inflammatory cytokines such as TNF and IFNs even in non-classical immune cells 31 263 268…”

“…For instance, a subset of IFNγ-activated genes encoding guanylate binding proteins (GBPs) can maintain a heritable open chromatin state at their promoter region in the absence of active transcription after priming. On re-exposure to IFNγ,263 the primed state leads to enhanced GBP expression via STAT1-signalling. Similarly, activation of STAT3 is essential to establish epigenetic memory in EpSCs 269.…”

Transcriptional memory is conferred by combined heritable maintenance and local removal of selective chromatin modifications

“…We sought to discover the mechanism driving transcriptional memory at GBP genes. We previously found that trans-acting factors including upstream IFNγ signalling, JAK kinase activity, Polymerase II occupancy and activation of the key downstream transcription factor STAT1 are not the carriers of long-term memory 10 . Similarly, cis-acting chromatin features that are associated with active gene expression, including an increase in chromatin accessibility, H3K27 acetylation and H3K36 trimethylation are only transiently associated with GBP genes but return to baseline levels upon loss of expression 8 .…”