phaidra.vetmeduni.ac.at o:5407 DOI 10.1186/s12864-026-12601-5 IFNγ shapes macrophage inflammatory responses by STAT1 isoform-specific epigenetic and transcriptional mechanisms Interferon-γ (IFNγ) is a key cytokine that activates macrophages and is essential for the defence against intracellular pathogens. Beyond its immediate effects, IFNγ also shapes macrophages for subsequent encounters with pathogen-associated molecules by multiple mechanisms, including chromatin remodelling. Here, we employed integrated epigenomic and transcriptomic approaches utilizing primary macrophages from gene-modified mice to explore the role of STAT1 and its naturally occurring isoforms in these processes. Using ChIP-seq for histone modifications (H3K27ac and H3K4me1) and RNA-seq, we demonstrate that STAT1 isoforms differentially modulate macrophage responses to lipopolysaccharide (LPS) following IFNγ conditioning. We provide genetic evidence that STAT1 isoforms exhibit distinct capacities to mediated IFNγ-induced changes in H3K27 acetylation at promoter and enhancer regions, thereby shaping transcriptional responses to LPS. We show that the STAT1β isoform, which lacks the C-terminal transactivation domain (TAD), is unable to mediate the repressive effect of IFNγ on transcriptional regulation by LPS but retains significant collaborative activity. Furthermore, we show that IFNγ attenuates the induction of a subset of antiviral genes and represses LPS-induced negative feedback loops, thereby amplifying the inflammatory response to pathogens. These effects are dependent on the presence of the STAT1 C-terminal TAD, highlighting its importance in fine-tuning the balance between inflammatory and antiviral responses. Our findings uncover isoform-specific roles of STAT1 in IFNγ-driven epigenetic regulation and macrophage conditioning, providing new insights into the control of inflammation and innate immunity. eng Interferon- γ Lipopolysaccharide (LPS) Macrophage Conditioning H3K27ac H3K4me1 RNA-seq 2026-08-11T10:04:28.054Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Akagha;Mojoyinola Joanna; FN:Mojoyinola Joanna Akagha END:VCARD BEGIN:VCARD VERSION:3.0 N:Georgolopoulos;Grigorios; FN:Grigorios Georgolopoulos END:VCARD BEGIN:VCARD VERSION:3.0 N:Martin;David; FN:David Martin END:VCARD BEGIN:VCARD VERSION:3.0 N:Meissl;Katrin; FN:Katrin Meissl END:VCARD BEGIN:VCARD VERSION:3.0 N:Amenitsch;Lena; FN:Lena Amenitsch X-ORCID:https://orcid.org/0000-0003-4873-1155 END:VCARD BEGIN:VCARD VERSION:3.0 N:Vogl;Claus; FN:Claus Vogl X-ORCID:https://orcid.org/0000-0002-3996-7863 END:VCARD BEGIN:VCARD VERSION:3.0 N:Farlik;Matthias; FN:Matthias Farlik END:VCARD BEGIN:VCARD VERSION:3.0 N:Fortelny;Nikolaus; FN:Nikolaus Fortelny END:VCARD BEGIN:VCARD VERSION:3.0 N:Halbritter;Florian; FN:Florian Halbritter END:VCARD BEGIN:VCARD VERSION:3.0 N:Müller;Mathias; FN:Mathias Müller X-ORCID:https://orcid.org/0000-0002-7879-3552 END:VCARD BEGIN:VCARD VERSION:3.0 N:Decker;Thomas; FN:Thomas Decker END:VCARD BEGIN:VCARD VERSION:3.0 N:Strobl;Birgit; FN:Birgit Strobl X-ORCID:https://orcid.org/0000-0001-5716-3212 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 8619435 https://phaidra.vetmeduni.ac.at/o:5407 https://phaidra.vetmeduni.ac.at/api/object/o:5407/thumbnail LOMv1.0 discipline