Transcriptional networking of STAT1 isoforms

NETWORK CONTRIBUTION

Most STAT proteins exist as a full-length α-isoform and a β-isoform that lacks the C-terminal transactivation domain (TAD). Although it is established that the β-isoforms are transcriptionally active, their mechanism of action and specificity are unclear. We will investigate the role of the individual STAT1 isoforms in different layers of gene regulation, including the establishment/activation of enhancers, networking with other TFs, interaction with co-factors and recruitment of the basal transcriptional machinery. The work will be performed in bone marrow-derived macrophages (under basal conditions and in response to IFNγ).

Our major goal is to evaluate the functional consequences on gene expression when naïve CD4+ T cells are activated, building on the finding that STAT1 isoforms are subject to a unique regulation in T cells.

Within the proposed project we investigate STAT1 isoform-specific TF and chromatin regulatory functions.

CONTACT

Department of Biomedical Sciences, Institute of Animal Breeding and Genetics
University of Veterinary Medicine Vienna, Vetmeduni Vienna

A-1210 Vienna
Austria

birgit.strobl@vetmeduni.ac.at

PUBLICATIONS

SFB-F61 / F28 related publications - Group Strobl

Prchal, M, Pilz, A., Simma, O., Lingnau, K., von Gabain, A., Strobl, B., Müller, M., and Decker, T. (2009).
Type I interferons as mediators of immune adjuvants for T- and B cell- dependent acquired immunity.
Vaccine 27 Suppl 6, G17-20. doi: 10.1016/j.vaccine.2009.10.016
Radwan*, M., Stiefvater*, R., Grunert, T., Sharif, O., Miller, I., Marchetti-Deschmann, M., Allmaier, G., Gemeiner, M., Knapp, S., Kovarik§, P., Müller, M., and Strobl, B. (2010). *equal contribution §SFB member of the 1st funding period
Tyrosine kinase 2 controls IL-1beta production at the translational level.
J Immunol 185: 3544-3553. doi: 10.4049/jimmunol.0904000
Vogl, C., Flatt, T., Fuhrmann, B., Hofmann, E., Wallner, B., Stiefvater, R., Kovarik, P., Strobl, B., and Müller, M. (2010).
Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes.
BMC Genomics 11: 199. doi: 10.1186/1471-2164-11-199
Strobl, B., Stoiber, D., Sexl, V., and Müller, M. (2011).
Tyrosine kinase 2 (Tyk2) in cytokine signalling and host immunity.
Front Biosci 17: 3224-3232. [review] doi: http://dx.doi.org/10.2741/3908
Blanc, M., Hsieh, W., Robertson, K., Watterson, S., Shui, G., Lacaze, P., Khondoker, M., Dickinson, P., Sing, G., Rodriguez-Martin, S., Phelan, P., Forster, T., Strobl, B., Müller, M., Riemersma, R., Osborne, T., Wenk, M.R., Angulo, A., and Ghazal, P. (2011).
Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis.
PLoS Biol 9: e1000598. doi: 10.1371/journal.pbio.1000598
Grunert, T., Leitner, N.R., Marchett-Deschmann, M., Miller, I., Wallner, B., Radwan, M., Vogl, C., Kolbe, T., Kratky, D., Gemeiner, M., Allmaier, G., Müller, M., and Strobl, B. (2011).
A comparative proteome analysis links tyrosine kinase 2 (Tyk2) to the regulation of cellular glucose and lipid metabolism in response to poly(I:C).
J Proteomics 74: 2866-2880. doi: 10.1016/j.jprot.2011.07.006
Kropp, K.A., Robertson, K.A., Sing, G., Rodriguez-Martin, S., Blanc, M., Lacaze, P., Noor Hassim, M.F.B., Khondoker, M.R., Busche, A., Dickinson, P., Forster, T., Strobl, B., Müller, M., Jonjic, S., Angulo, A., and Ghazal, P. (2011).
Reversible inhibition of MCMV replication by IFN{gamma} in primary macrophages involves a primed type I IFN signaling sub-network for full establishment of an immediate-early antiviral-state.
J Virol 85: 10286-10299. doi: 10.1128/JVI.00373-11
Hofmann, E., Reichart, U., Gausterer, C., Gülly, C., Meijer, D., Müller, M., and Strobl, B. (2010).
Octamer-binding factor 6 (Oct-6/Pou3f1) is induced by interferon and contributes to dsRNA-mediated transcriptional responses.
BMC Cell Biol 11: 61. doi: 10.1186/1471-2121-11-61
Mizutani*, T., Neugebauer*, N., Putz*, E.M., Moritz, N., Simma, O., Zebedin-Brandl, E., Gotthardt, D., Warsch, W., Eckelhart, E., Kantner, H.-P., Kalinke, U., Lienenklaus, S., Weiss, S., Strobl, B., Müller, M., Sexl, V., and Stoiber, D. (2012). *equal contribution
Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance.
Oncoimmunology 1: 1027-1037. doi: 10.4161/onci.21284
Prchal-Murphy, M., Semper, C., Lassnig, C., Wallner, B., Gausterer, C., Teppner-Klymiuk, I., Kobolak, J., Müller, S., Kolbe, T., Karaghiosoff, M., Dinnyes, A., Rülicke, T., Leitner, N.R., Strobl, B., and Müller, M. (2012).
TYK2 Kinase Activity Is Required for Functional Type I Interferon Responses In Vivo.
PLoS One 7: e39141. doi: 10.1371/journal.pone.0039141
Derecka, M., Gornicka, A., Koralov, S.B., Szczepanek, K., Morgan, M., Raje, V., Sisler, J., Zhang, Q., Otero, D., Cichy, J., Rajewsky, K., Shimoda, K., Poli, V., Strobl, B., Pellegini, S., Harris, T.E., Seale, P., Russell, A.P., McAinch, A.J., O'Brien, P.E., Keller, S., Croniger, C.M., Kordula, T., and Larner, A.C. (2012).
Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity.
Cell Metab 16: 814-824. doi: 10.1016/j.cmet.2012.11.005
Strobl, B., Leitner, N.R., and Müller, M. (2012).
Multifaceted Antiviral Actions of Interferon-Stimulated Gene Products.
In Jak-Stat Signaling: From Basics to Disease. (Decker, T. and Müller, M., Eds.) Springer Wien Heidelberg New York Dordrecht London. pp. 387-424. [book chapter] doi: 10.1007/978-3-7091-0891-8_21 ISBN: 978-3-7091-0890-1
Warszawska, J.M., Gawish, R., Sharif, O., Sigel, S., Doninger, B., Lakovits, K., Mesteri, I., Nairz, M., Boon, L., Spiel, A., Fuhrmann, V., Strobl, B., Müller, M., Schenk, P., Weiss, G., and Knapp, S. (2013).
Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes.
J Clin Invest 123: 3363-3372. doi: 10.1172/JCI67911
Bancerek, J., Poss, Z.C., Steinparzer, I., Sedlyarov, V., Pfaffenwimmer, T., Mikulic, I., Dölken, L., Strobl, B., Müller, M., Taatjes, D.J., and Kovarik§, P. (2013). §SFB member of the 1st funding period
CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response.
Immunity 38: 250-262. doi: 10.1016/j.immuni.2012.10.017
Bosmann, M., Strobl, B., Kichler, N., Pache, F., Murray, P.J., Müller, M., and Ward, P.A. (2014).
Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production of interleukin-27.
J Leukoc Biol. 96: 123-131. doi: 10.1189/jlb.3A1013-541R
Gotthardt, D., Putz, E.M., Straka, E., Kudweis, P., Biaggio, M., Poli, V., Strobl, B., Müller, M., and Sexl, V. (2014).
Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.
Blood 124: 2370-2379. doi: http://dx.doi.org/10.1182/blood-2014-03-564450
Grunert, T., Monahan, A., Lassnig, C., Vogl, C., Strobl, B., Müller, M., and Ehling-Schulz, M. (2014).
Deciphering host genotype-specific impacts on the metabolic fingerprint of Listeria monocytogenes by FTIR spectroscopy.
PLoS One 9: e115959. doi: 10.1371/journal.pone.0115959
Keil, E., Finkenstädt, D., Wufka, C., Trilling, M., Liebfried, P., Strobl, B., Müller, M., and Pfeffer, K. (2014).
Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation loop mutation.
Blood 123: 520-529. doi: http://dx.doi.org/10.1182/blood-2013-03-492157
Leitner, N.R., Lassnig, C., Rom, R., Heider, S., Bago-Horvath, Z., Eferl§, R., Müller, S., Kolbe, T., Kenner, L., Rülicke, T., Strobl, B., and Müller, M. (2014). §SFB member of the 1st and 2nd funding period
Inducible, dose-adjustable and time-restricted reconstitution of Stat1 deficiency in vivo.
PLoS One 9: e86608. doi: 10.1371/journal.pone.0086608
Liehl, P., Zuzarte-Luís, V., Chan, J., Zillinger, T., Baptista, F., Carapau, D., Konert, M., Hanson, K.K., Carret, C., Lassnig, C., Müller, M., Kalinke, U., Saeed, M., Ferreira Chora, A., Golenbock, D.T., Strobl, B., Prudencio, M., Coelho, L.P., Kappe, S.H., Superti-Furga, J., Pichlmair, A., Vigário, A.M., Rice, C.M., Fitzgerald, K.A., Barchert, W., and Mota, M.M. (2014).
Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.
Nat Med 20: 47-53. doi: 10.1038/nm.342
Semper, C., Leitner, N.R., Lassnig, C., Parrini, M., Mahlakoiv, T., Rammerstorfer, M., Lorenz, K., Rigler, D., Müller, S., Kolbe, T., Vogl, C., Rülicke, T., Staeheli, P., Decker, T., Müller, M., and Strobl, B. (2014).
STAT1β is not dominant negative and is capable of contributing to IFNγ-dependent innate immunity.
Mol Cell Biol 34: 2235-2248. doi: 10.1128/MCB.00295-14
Vielnascher, R.M., Hainzl, E., Leitner, N.R., Rammerstorfer, M., Popp, D., Witalisz, A., Rom, R., Karaghiosoff, M., Kolbe, T., Müller, S., Rülicke, T., Lassnig, C., Strobl, B., and Müller, M. (2014).
Conditional ablation of TYK2 in immunity to viral infection and tumor surveillance.
Transgenic Res. 23: 519-529. doi: 10.1007/s11248-014-9795-y
Strobl, B., and Moriggl, R. (2014).
Editorial: Recovery from chemotherapy depends on STAT1 for replenishment of B lymphopoiesis.
J Leukocyte Biol 95: 849-851. [editorial review] doi: 10.1189/jlb.0114051
Pathria*, P., Gotthardt*, D., Prchal-Murphy*, M., Putz*, E.M., Holcmann, M., Schlederer, M., Grabner, B., Crncec, I., Svinka, J., Musteanu, M., Hoffmann, T., Filipits, M., Berger, W., Poli, V., Kenner, L., Bilban, M., Casanova, E., Müller, M., Strobl, B., Bayer, E., Mohr, T., Sexl, V., and Eferl§, R. (2015). *equal contribution §SFB member of the 1st and 2nd funding period
Myeloid STAT3 promotes formation of colitis-associated colorectal cancer in mice.
Oncoimmunology 4(4):e998529. doi: 10.1080/2162402X.2014.998529
Prchal-Murphy, M., Witalisz-Siepracka, A., Bednarik, K.T., Putz, E.M., Gotthardt, D., Meissl, K., Sexl, V., Müller, M., and Strobl, B. (2015).
In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity.
Oncoimmunology. doi: 10.1080/2162402X.2015.1047579
Wienerroither, S., Shukla, P., Farlik, M., Majoros, A., Stych, B., Vogl, C., Cheon, H., Stark, G.R., Strobl, B., Müller, M., and Decker, T. (2015).
Cooperative transcriptional activation of antimicrobial genes by STAT and NFκB pathways through concerted recruitment of the mediator complex.
Cell Reports 12: 1-13. doi: http://dx.doi.org/10.1016/j.celrep.2015.06.021
Wiesauer, I., Gaumannmuller, C., Steinparzer, I., Strobl, B., and Kovarik§, P. (2015). §SFB member of the 1st funding period
Promoter occupancy of STAT1 in interferon responses is regulated by processive transcription.
Mol Cell Biol 35: 716-727. doi: 10.1128/MCB.01097-14
Bauer, E., Witalisz, A., Strobl, B., and Stoiber, D. (2015).
Methods to study tumor surveillance using tumor cell transplantation into genetically engineered mice.
Methods Mol Biol 1267: 439-456. [review] doi: 10.1007/978-1-4939-2297-0_22

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