Ludwig Michael P, Wilson Jason R, Galbraith Matthew D, Bhandari Nirajan, Dunn Lauren N, Black Joshua C, Sullivan Kelly D
Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
These Authors Contributed Equally.
bioRxiv. 2025 Mar 13:2025.03.11.641929. doi: 10.1101/2025.03.11.641929.
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-κB 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.
细胞对病原体的反应涉及由关键的固有免疫信号通路指导的复杂反应，其特征是细胞间的异质性。这种异质性是如何建立和调控的仍不清楚。我们描述了一个瞬时位点特异性增益（TSSG）程序，该程序可响应固有免疫信号产生免疫相关基因的染色体外DNA（ecDNA）。NF-κB的激活通过将转录因子RelA和复制前复合体成员MCM2诱导募集到表观遗传调控的TSSG控制元件，驱动干扰素受体基因簇的TSSG。RelA或p300的靶向募集足以诱导TSSG形成。RelA和MCM2为至少6个且多达179个富含固有免疫反应基因的区域指定了TSSG程序。对该程序的鉴定揭示了ecDNA的调控产生是宿主反应中异质性的一种机制。
