Dynamic control of gene expression by ISGF3 and IRF1 during IFNβ and IFNγ signaling

Type I interferons (IFN-I, including IFN beta) and IFN gamma produce overlapping, yet clearly distinct immunological activities. Recent data show that the distinctness of global transcriptional responses to the two IFN types is not apparent when comparing their immediate effects. By analyzing nascent transcripts induced by IFN-I or IFN gamma over a period of 48 h, we now show that the distinctiveness of the transcriptomes emerges over time and is based on differential employment of the ISGF3 complex as well as of the second-tier transcription factor IRF1. The distinct transcriptional properties of ISGF3 and IRF1 correspond with a largely diverse nuclear protein interactome. Mechanistically, we describe the specific input of ISGF3 and IRF1 into enhancer activation and the regulation of chromatin accessibility at interferon-stimulated genes (ISG). We further report differences between the IFN types in altering RNA polymerase II pausing at ISG 5' ends. Our data provide insight how transcriptional regulators create immunological identities of IFN-I and IFN gamma. Type I interferons (IFN) and IFN gamma have different immunological activities. This study finds that although their signals and transcriptome changes early after receptor engagement are very similar, they diverge in the later stages of the response to produce transcriptomes consistent with their diverse function.The early response to both IFN types is dominated by the STAT1/2/IRF9 complex called ISGF3. Interferon regulatory factor 1 (IRF1) is induced by both IFN types, but transiently by type I IFN and in a sustained manner by IFN gamma. Late-stage responses to type I IFN are still largely dominated by the ISGF3 complex, whereas IRF1 plays an important role for delayed and sustained transcriptome changes in response to IFN gamma. Higher order responses by transcription factors other than IRF1 are likely to contribute to delayed and sustained transcriptional induction by both IFN types as well. Cell-autonomous immunity triggered by type I interferons and IFN gamma cause distinct transcriptional programms, which diverge over time to produce specific cellular responses. Type I interferons (IFN-I, including IFNβ) and IFNγ produce overlapping, yet clearly distinct immunological activities. Recent data show that the distinctness of global transcriptional responses to the two IFN types is not apparent when comparing their immediate effects. By analyzing nascent transcripts induced by IFN-I or IFNγ over a period of 48 h, we now show that the distinctiveness of the transcriptomes emerges over time and is based on differential employment of the ISGF3 complex as well as of the second-tier transcription factor IRF1. The distinct transcriptional properties of ISGF3 and IRF1 correspond with a largely diverse nuclear protein interactome. Mechanistically, we describe the specific input of ISGF3 and IRF1 into enhancer activation and the regulation of chromatin accessibility at interferon-stimulated genes (ISG). We further report differences between the IFN types in altering RNA polymerase II pausing at ISG 5' ends. Our data provide insight how transcriptional regulators create immunological identities of IFN-I and IFNγ.© 2024. The Author(s).

Evotec
Max F. Perutz Laboratories GmbH
Medizinische Universität Wien - AKH
Universität Wien
Veterinärmedizinische Universität Wien