Abstract
Interferon-stimulated genes (ISGs) are the effectors of interferon (IFN) actions and play major roles in innate immune defense against microbial infection. During virus infection, ISGs impart antiviral actions to control virus replication and spread but can also contribute to disease pathology if their expression is unchecked. Antiviral ISGs have been identified by a variety of biochemical, genetic, and virologic methods. New computational approaches are expanding and redefining ISGs as responders to a variety of stimuli beyond IFNs, including virus infection, stress, and other events that induce cytokines. These studies reveal that the expression of ISG subsets link to interferon regulatory factors (IRF)s, NF-kB, and other transcription factors that impart gene expression in specific cell types independently of IFNs, including stem cells and other cell types where ISGs are constitutively expressed. Here, we provide a broad overview of ISGs, define virus-induced genes (VSG)s, and discuss the application of computational approaches and bioinformatics platforms to evaluate the functional role of ISGs in epigenetics, immune programming, and vaccine responses.
Similar content being viewed by others
References
Barrenas F, Green RR, Thomas MJ, Law GL, Proll SC et al (2015) Next-generation sequencing reveals a controlled immune response to Zaire Ebola virus challenge in cynomolgus macaques immunized with vesicular stomatitis virus expressing Zaire Ebola virus glycoprotein (VSV∆G/EBOVgp). Clin Vaccine Immunol 22(3):354–356
Becker M, De Bastiani MA, Parisi MM, Guma FT, Markoski MM et al (2015) Integrated transcriptomics establish macrophage polarization signatures and have potential applications for clinical health and disease. Sci Rep 5:13351
Bertolusso R, Tian B, Zhao Y, Vergara L, Sabree A et al (2014) Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. PLoS ONE 9(4):e93396
Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM et al (2007) Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov 6(12):975–990
Chang JJ, Woods M, Lindsay RJ, Doyle EH, Griesbeck M et al (2013) Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication. J Infect Dis 208(5):830–838
Chistiakov DA, Myasoedova VA, Revin VV, Orekhov AN, Bobryshev YV (2018) The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2. Immunobiology 223(1):101–111
Chow KT, Gale M Jr (2015) SnapShot: interferon signaling. Cell 163(7):1808–1808.e1
Crow MK (2016) Autoimmunity: interferon α or β: which is the culprit in autoimmune disease? Nat Rev Rheumatol 12(8):439–440
Cui K, Tailor P, Liu H, Chen X, Ozato K et al (2004) The chromatin-remodeling BAF complex mediates cellular antiviral activities by promoter priming. Mol Cell Biol 24(10):4476–4486
DaFonseca CJ, Shu F, Zhang JJ (2001) Identification of two residues in MCM5 critical for the assembly of MCM complexes and Stat1-mediated transcription activation in response to IFN-gamma. Proc Natl Acad Sci USA 98(6):3034–3039
de Veer MJ, Holko M, Frevel M, Walker E, Der S et al (2001) Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol 69(6):912–920
Der SD, Zhou A, Williams BR, Silverman RH (1998) Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci USA 95(26):15623–15628
Dixit E, Boulant S, Zhang Y, Lee AS, Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan SP, Fransen M, Nibert ML, Superti-Furga G, Kagan JC (2010) Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141(4):668–681. https://doi.org/10.1016/j.cell.2010.04.018
Doganay S, Lee MY, Baum A, Peh J, Hwang SY et al (2017) Single-cell analysis of early antiviral gene expression reveals a determinant of stochastic IFNB1 expression. Integr Biol 9(11):857–867
Forero A, Fenstermacher K, Wohlgemuth N, Nishida A, Carter V et al (2017) Evaluation of the innate immune responses to influenza and live-attenuated influenza vaccine infection in primary differentiated human nasal epithelial cells. Vaccine 35(45):6112–6121
Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai SL, Arepalli S, Dillman A, Rafferty IP, Troncoso J, Johnson R, Zielke HR, Ferrucci L, Longo DL, Cookson MR, Singleton AB (2010) Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 6(5):e1000952. https://doi.org/10.1371/journal.pgen.1000952
Grandvaux N, Servant MJ, tenOever B, Sen GC, Balachandran S et al (2002) Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J Virol 76(11):5532–5539
Green R, Wilkins C, Thomas S, Sekine A, Ireton RC et al (2016) Identifying protective host gene expression signatures within the spleen during West Nile virus infection in the collaborative cross model. Genom Data 10:114–117
Grubert F, Zaugg JB, Kasowski M, Ursu O, Spacek DV, Martin AR, Greenside P, Srivas R, Phanstiel DH, Pekowska A, Heidari N, Euskirchen G, Huber W, Pritchard JK, Bustamante CD, Steinmetz LM, Kundaje A, Snyder M (2015) Genetic control of chromatin states in humans involves local and distal chromosomal interactions. Cell 162(5):1051–1065. https://doi.org/10.1016/j.cell.2015.07.048
Hemann EA, Gale M Jr, Savan R (2017) Interferon lambda genetics and biology in regulation of viral control. Front Immunol 8:1707
Henle W (1950) Interference phenomena between animal viruses: a review. J Immunol 64(3):203–236
Hertzog P, Forster S, Samarajiwa S (2011) Systems biology of interferon responses. J Interferon Cytokine Res 31(1):5–11
Huang M, Qian F, Hu Y, Ang C, Li Z et al (2002) Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes. Nat Cell Biol 4(10):774–781
Hung JH, Yang TH, Hu Z, Weng Z, DeLisi C (2012) Gene set enrichment analysis: performance evaluation and usage guidelines. Brief Bioinform 13(3):281–291
Isaacs A, Lindenmann J, Valentine RC (2015) Pillars article: virus interference II some properties of interferon. Proc R Soc Lond B Biol Sci. 1957. 147:268–273. J Immunol 195(5):1921–1926
Iwanaszko M, Kimmel M (2015) NF-κB and IRF pathways: cross-regulation on target genes promoter level. BMC Genom 16:307
Jiang L, Li X, Zhang Y, Zhang M, Tang Z et al (2017) Microarray and bioinformatics analyses of gene expression profiles in BALB/c murine macrophage polarization. Mol Med Rep 16(5):7382–7390
Kang HM, Ye C, Eskin E (2008) Accurate discovery of expression quantitative trait loci under confounding from spurious and genuine regulatory hotspots. Genetics 180(4):1909–1925. https://doi.org/10.1534/genetics.108.094201
Lachmann A, Torre D, Keenan AB, Jagodnik KM, Lee HJ et al (2018) Massive mining of publicly available RNA-seq data from human and mouse. Nat Commun 9(1):1366
Lau JF, Nusinzon I, Burakov D, Freedman LP, Horvath CM (2003) Role of metazoan mediator proteins in interferon-responsive transcription. Mol Cell Biol 23(2):620–628
Liu L, Wei J, Ruan J (2017) Pathway enrichment analysis with networks. Genes 8(10):246
Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C, Nisbett J, Guigo R, Dermitzakis ET (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464(7289):773–777. https://doi.org/10.1038/nature08903
Moschonas A, Ioannou M, Eliopoulos AG (2012) CD40 stimulates a “feed-forward” NF-κB-driven molecular pathway that regulates IFN-β expression in carcinoma cells. J Immunol 188(11):5521–5527
Mostafavi S, Yoshida H, Moodley D, LeBoité H, Rothamel K et al (2016) Parsing the interferon transcriptional network and its disease associations. Cell 164(3):564–578
Ni Z, Karaskov E, Yu T, Callaghan SM, Der S et al (2005) Apical role for BRG1 in cytokine-induced promoter assembly. Proc Natl Acad Sci USA 102(41):14611–14616
Parts L, Stegle O, Winn J, Durbin R (2011) Joint genetic analysis of gene expression data with inferred cellular phenotypes. PLoS Genet 7(1):e1001276. https://doi.org/10.1371/journal.pgen.1001276
Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE, Nkadori E, Veyrieras JB, Stephens M, Gilad Y, Pritchard JK (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464(7289):768–772. https://doi.org/10.1038/nature08872
Pott J, Stockinger S (2017) Type I and III interferon in the gut: tight balance between host protection and immunopathology. Front Immunol 8:258
Probst P, Grigg JB, Wang M, Muñoz E, Loo YM et al (2017) A small-molecule IRF3 agonist functions as an influenza vaccine adjuvant by modulating the antiviral immune response. Vaccine 35(15):1964–1971
Querec TD, Akondy RS, Lee EK, Cao W, Nakaya HI, Teuwen D, Pirani A, Gernert K, Deng J, Marzolf B, Kennedy K, Wu H, Bennouna S, Oluoch H, Miller J, Vencio RZ, Mulligan M, Aderem A, Ahmed R, Pulendran B (2009) Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 10(1):116–125. https://doi.org/10.1038/ni.1688
Raftery N, Stevenson NJ (2017) Advances in anti-viral immune defence: revealing the importance of the IFN JAK/STAT pathway. Cell Mol Life Sci 74(14):2525–2535
Rakitsch B, Stegle O (2016) Modelling local gene networks increases power to detect trans-acting genetic effects on gene expression. Genome Biol 17:33. https://doi.org/10.1186/s13059-016-0895-2
Rodero MP, Crow YJ (2016) Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med 213(12):2527–2538
Rusinova I, Forster S, Yu S, Kannan A, Masse M et al (2013) Interferome v20: an updated database of annotated interferon-regulated genes. Nucleic Acids Res 41(Database issue):D1040–D1046
Samarajiwa SA, Forster S, Auchettl K, Hertzog PJ (2009) INTERFEROME: the database of interferon regulated genes. Nucleic Acids Res 37(Database issue):D852–D857
Sarkar SN, Sen GC (2004) Novel functions of proteins encoded by viral stress-inducible genes. Pharmacol Ther 103(3):245–259
Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513–545
Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT et al (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472(7344):481–485
Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B et al (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505(7485):691–695
Schroder K, Hertzog PJ, Ravasi T, Hume DA (2004) Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75(2):163–189
Shaw AE, Hughes J, Gu Q, Behdenna A, Singer JB et al (2017) Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses. PLoS Biol 15(12):e2004086
Sohn JI, Nam JW (2018) The present and future of de novo whole-genome assembly. Brief Bioinform 19(1):23–40
Stark GR, Darnell JE Jr (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503–514
Stegle O, Parts L, Durbin R, Winn J (2010) A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comput Biol 6(5):e1000770. https://doi.org/10.1371/journal.pcbi.1000770
van de Garde MDB, Pas SD, van Oord GW, Gama L, Choi Y et al (2017) Interferon-alpha treatment rapidly clears Hepatitis E virus infection in humanized mice. Sci Rep 7(1):8267
Waszak SM, Delaneau O, Gschwind AR, Kilpinen H, Raghav SK, Witwicki RM, Orioli A, Wiederkehr M, Panousis NI, Yurovsky A, Romano-Palumbo L, Planchon A, Bielser D, Padioleau I, Udin G, Thurnheer S, Hacker D, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2015) Population variation and genetic control of modular chromatin architecture in humans. Cell 162(5):1039–1050. https://doi.org/10.1016/j.cell.2015.08.001
Webster B, Assil S, Dreux M (2016) Cell-cell sensing of viral infection by plasmacytoid dendritic cells. J Virol 90(22):10050–10053
Yan Z, Cui K, Murray DM, Ling C, Xue Y et al (2005) PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev 19(14):1662–1667
Zhang JJ, Zhao Y, Chait BT, Lathem WW, Ritzi M et al (1998) Ser727-dependent recruitment of MCM5 by Stat1alpha in IFN-gamma-induced transcriptional activation. EMBO J 17(23):6963–6971
Zhu M, John S, Berg M, Leonard WJ (1999) Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Cell 96(1):121–130
Acknowledgements
Supported by National Institutes of Health Grants U19AI100625, R01AI104002, and U19AI083019. The funders had no role in the design, data acquisition, analysis, or preparation of the manuscript. Thanks to Amy Green for proof reading. Thanks to Adrianna Forero for her support and critical insights.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Rights and permissions
About this article
Cite this article
Green, R., Ireton, R.C. & Gale, M. Interferon-stimulated genes: new platforms and computational approaches. Mamm Genome 29, 593–602 (2018). https://doi.org/10.1007/s00335-018-9755-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-018-9755-6