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The hypoxia-inducible transcription factor ZNF395 is controlled by I-kappaB kinase and activates genes involved in the innate immune response and cancer

ABSTRACT: Activation of the hypoxia inducible transcription factor HIF-alpha and the NF-kappaB pathway promotes inflammation mediated tumor progression. The cellular transcription factor ZNF395 was repeatedly found over expressed in various human cancers and particularly in response to hypoxia, implying a functional relevance. To understand the biological activity of ZNF395, we identified target genes of ZNF395 by a genome-wide expression screen. Induced ZNF395 expression let to up-regulation of a subset of interferon (IFN)-responsive genes such as IFIT1/ISG56 and IFI44 as well as genes known to be involved in cancer progression including MEF2C and MACC1. ZNF395 requires its DNA binding domain and the two IFN-sensitive-response elements within the IFIT1/ISG56 promoter to activate. We provide evidence that IkBa kinase-mediated phosphorylation is required to allow activation of transcription by ZNF395 but simultaneously accelerates it for proteolytic degradation to keep the activity of ZNF395 transient and weak. We further confirm that ZNF395 is induced by hypoxia. Thus, two crucial pathways contributing to cancers progression, i.e. hypoxia and inflammation cooperate in activation of ZNF395 at the level of transcription and post-translational modification. Increased amounts of transcriptional active ZNF395 in cancers may support carcinogenesis by activating its target genes associated with the innate immune response and cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44327 | GEO | 2014/03/01

SECONDARY ACCESSION(S): PRJNA189474

REPOSITORIES: GEO

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Project description:Maier2022 - Stochastic Dynamics of Type I Interferon Responses Our study aims to determine whether and how biochemical noise affects the information transduced in the JAK-STAT signaling pathway and investigate the transition between basal and activated state. To this end, we studied the stochastic responses of MxA and IFIT1 expression in Huh7.5 cells stimulated with IFN-$\alpha$. Using fluorescent reporters under the control of the authentic promoter/enhancer region of IFIT1 and MxA we collected data displaying the differences between expressing and non-expressing cells for the marker genes in a time-course experiment. We hypothesize that the JAK-STAT signaling pathway efficiently transmits information under stochastic environments. To test our working hypothesis, we developed a detailed mathematical model using the obtained time-resolved flow cytometry data to describe the elements in the JAK-STAT signaling pathway at single-cell resolution. This model allowed us to systematically test the influence of intrinsic and extrinsic noise in the IFN response. The developed model consists of 42 species and 62 reactions (reactions m1 to m62). To name the variables in the model we used the following conventions: 1) variables referring to mRNA are denoted by $m$ prefix. 2) Variables in phosphorylated use $p$ as prefix. 3) Gene promoters are represented by the gene's name in lowercase. 4) R1, R2, IR, AR and RC, represent the IFN receptor subunits, inactive, active and complex forms, respectively. 5) The compartment is superscripted to the species if the species exist in multiple compartments. A graphical representation of the interaction between variables in the model is given in Maier et. al 2022 (Fig. 1) and all reactions are listed in the Supplementary Information, Section S2.1. Note that we publish the SBML model without the observables (e.g. exp_IRF9_n) as the change in the number of particles is defined in relation to the starting value in the COPASI model which is not supported in SBML format. In order to reproduce the parameter estimation without any extra worj, we recommend the direct download of the provided copasi model linked in the article. This model is described in the article: Stochastic Dynamics of Type I Interferon Responses Benjamin D. Maier(*), Luis U. Aguilera(*), Sven Sahle, Pascal Mutz, Priyata Kalra, Christopher Dächert, Ralf Bartenschlager, Marco Binder, Ursula Kummer PLOS Computational Biology, 2022 (*) Equally contributing authors Abstract: Interferon (IFN) activates the transcription of several hundred of IFN stimulated genes (ISGs) that constitute a highly effective antiviral defense program. Cell-to-cell variability in the induction of ISGs is well documented, but its source and effects are not completely understood. The molecular mechanisms behind this heterogeneity have been related to randomness in molecular events taking place during the JAK-STAT signaling pathway. Here, we study the sources of variability in the induction of the IFN-alpha response by using MxA and IFIT1 activation as read-out. To this end, we integrate time-resolved flow cytometry data and stochastic modeling of the JAK-STAT signaling pathway. The complexity of the IFN response was matched by fitting probability distributions to time-course flow cytometry snapshots. Both, experimental data and simulations confirmed that the MxA and IFIT1 induction circuits generate graded responses rather than all-or-none responses. Subsequently, we quantify the size of the intrinsic variability at different steps in the pathway. We found that stochastic effects are transiently strong during the ligand-receptor activation steps and the formation of the ISGF3 complex, but negligible for the final induction of the studied ISGs. We conclude that the JAK-STAT signaling pathway is a robust biological circuit that efficiently transmits information under stochastic environments.

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The hypoxia-inducible transcription factor ZNF395 is controlled by I-kappaB kinase and activates genes involved in the innate immune response and cancer

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