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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-\u03baB 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.<\/jats:p>","DOI":"10.1101\/2025.03.11.641929","type":"posted-content","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T23:50:21Z","timestamp":1741909821000},"source":"Crossref","is-referenced-by-count":0,"title":["NF-\u03baB signaling directs a program of transient amplifications at innate immune response genes"],"prefix":"10.64898","author":[{"given":"Michael P.","family":"Ludwig","sequence":"first","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason R.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew 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