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bioRxiv · 10.1101/2025.03.11.641929

NF-κB signaling directs a program of transient amplifications at innate immune response genes

Ludwig, M. P.·Wilson, J. R.·Galbraith, M. D.·Bhandari, N.·Dunn, L. N.·Black, J. C.·Sullivan, K. D.
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Abstract

The cellular response to pathogens involves an intricate response directed by key innate immune signaling pathways which is characterized by cell-to-cell heterogeneity. How this heterogeneity is established and regulated remains unclear. We describe a program of transient site-specific gains (TSSG) producing extrachromosomal DNA (ecDNA) of immune-related genes in response to innate immune signaling. Activation of NF-{kappa}B drives TSSG of the interferon receptor gene cluster through inducible recruitment of the transcription factor RelA and the pre-replication complex member MCM2 to an epigenetically regulated TSSG control element. Targeted recruitment of RelA or p300 are sufficient to induce TSSG formation. RelA and MCM2 specify a program of TSSG for at least six and as many as 179 regions enriched in innate immune response genes. Identification of this program reveals regulated production of ecDNA as a mechanism of heterogeneity in the host response.

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Ludwig, M. P., Wilson, J. R., Galbraith, M. D., Bhandari, N., Dunn, L. N., Black, J. C., Sullivan, K. D.. 2025-03-13. NF-κB signaling directs a program of transient amplifications at innate immune response genes. https://doi.org/10.1101/2025.03.11.641929

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