title: Opposing macrophage polarization programs show extensive epigenomic and transcriptional cross-talk.
abstract: Stimulation of macrophages with interferon-γ (IFN-γ) and interleukin 4 (IL-4) triggers distinct and opposing activation programs. During mixed infections or cancer, macrophages are often exposed to both cytokines, but how these two programs influence each other remains unclear. We found that IFN-γ and IL-4 mutually inhibited the epigenomic and transcriptional changes induced by each cytokine alone. Computational and functional analyses revealed the genomic bases for gene-specific cross-repression. For instance, while binding motifs for the transcription factors STAT1 and IRF1 were associated with robust and IL-4-resistant responses to IFN-γ, their coexistence with binding sites for auxiliary transcription factors such as AP-1 generated vulnerability to IL-4-mediated inhibition. These data provide a core mechanistic framework for the integration of signals that control macrophage activation in complex environmental conditions.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Piccolo
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Curina
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.affiliation: Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.affiliation: Humanitas Clinical and Research Center, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Simonatto
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Sabò
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Ostuni
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.|Department of Biomedical Sciences, School of Medicine, Humanitas University, Milan, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D007371:Interferon-gamma