Preprint Transcriptional memory is conferred by combined heritable maintenance and local removal of selective chromatin modifications, 2023, Mikulski et al.

SNT Gatchaman

SNT Gatchaman

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Transcriptional memory is conferred by combined heritable maintenance and local removal of selective chromatin modifications
Pawel Mikulski; Sahar S.H. Tehrani; Anna Kogan; Izma Abdul-Zani; Emer Shell; Brent J Ryan; Lars E.T. Jansen

Interferon-γ (IFNγ) transiently activates genes involved in inflammation and innate immunity. A subset of targets maintain a mitotically heritable memory of prior IFNγ exposure resulting in hyperactivation upon reexposure.

Here we discovered that the active chromatin marks H3K4me1, H3K14Ac and H4K16Ac are established during IFNγ priming and selectively maintained on a cluster of GBP genes for at least 7 days in dividing cells in the absence of transcription. The histone acetyltransferase KAT7 is required for the accelerated GBP reactivation upon reexposure to IFNγ. In naive cells, we find the GBP cluster is maintained in low-level repressive chromatin marked by H3K27me3 limiting priming in a PRC2-dependent manner. Unexpectedly, IFNγ results in transient accumulation of this repressive mark but is then selectively depleted from primed GBP genes during the memory phase facilitating hyperactivation of primed cells.

Furthermore, we identified a cis-regulatory element that makes transient, long-range contacts across the GBP cluster and acts as a repressor, primarily to curb the hyperactivation of previously IFNγ-primed cells.

Combined our results identify the putative chromatin basis for long-term transcriptional memory of interferon signalling that may contribute to enhanced innate immunity.


Link | PDF (Preprint: BioRxiv)
 
Despite the existence of transcriptional memory phenomena across multiple cellular processes and species, its molecular principles are obscure and represent an important gap in our understanding of gene expression regulation. Cellular exposure to the cytokine Interferon-gamma (IFNγ) is known to induce transcriptional memory
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In addition to the transient activation of a large number of genes, IFNγ induces long-term transcriptional memory of a subset of genes in different cell types [...]. We and others discovered that genes that display memory tend to reside in genomic clusters. One of these is a clustered family of genes encoding Guanylate-Binding Proteins (GBPs), GTPases that are crucial for inflammasome activation and protection against infections and cancer.
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While IFNγ results in only a transient activation of GBPs, cells maintain a heritable epigenetic memory of activation for up to 14 days of continued proliferation in the absence of target gene expression. This primed state results in hyperactivation of GBP genes upon re-exposure to IFNγ which may represent a crucial means for enhanced innate immune responses to repeated cellular insults.
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Our results are consistent with a model where the GBP memory loci selectively retain an epigenetically inherited chromatin signature after initial IFNγ stimulation, which in turn accelerates future expression hyperactivation upon IFNγ re-exposure. [...] Our results have broad mechanistic implications for the understanding of epigenetic memory of gene expression triggered by past exposure to the stimuli.
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Chromatin again
Chromatin fiber's genomic 'memory' governs the building blocks of life, study reveals
"
The scientists observed that chromatin self-organizes into "packing domains"—distinct, compact regions of molecular structures that play a crucial role in regulating gene expression.

"In the nucleus of each cell, the genome is folded in such a way as to form thousands of tiny nanoscale 'packing domains,' the three-dimensional structure of which creates 'memories' of transcription and which, amazingly, operates as a powerful geometric computational device—just like the reinforcement learning that powers neural networks in AI tools like ChatGPT and the behavior of cells in our brains," said Backman, who is also Associate Director for Engineering and Technology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University."


https://phys.org/news/2025-02-chromatin-fiber-genomic-memory-blocks.amp

https://www.science.org/doi/10.1126/sciadv.adq6652
 
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