IFN-Stimulated Gene 15 Is Synergistically Activated Through Interactions Between the Myelocyte/Lymphocyte-Specific Transcription Factors, PU.1, IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein, and IFN Regulatory Factor-4: Characterization of a New Subtype of IFN-Stimulated Response Element

Meraro, David; Gleit‐Kielmanowicz, Merav; Hauser, Hansjörg; Levi, Ben‐Zion

doi:10.4049/jimmunol.168.12.6224

Cited by 99 publications

(71 citation statements)

References 43 publications

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Section: Resultsmentioning

confidence: 99%

“…The composite element EIRE, which was overrepresented in monocytes, was shown previously to bind PU.1 and IRF8. 24,25 Whereas the latter is not drastically regulated on mRNA level, it is down-regulated on protein level during monocyte-to-macrophage differentiation ( Figure 3B), suggesting that IRF8 may be part of the monocyte-specific enhancer signature.Candidate transcription factors corresponding to the novel macrophage-specific motifs included the family of b-ZIP transcription factors, which are known to bind E-box elements. The macrophage-specific E-box element is similar to the M-box identified previously as the consensus binding site for the b-ZIP transcription factor microphthalmia (MITF).…”

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confidence: 99%

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Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

Pham

Benner

Lichtinger

et al. 2012

Blood

127

161

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Cellular differentiation is orchestrated by lineage-specific transcription factors and associated with cell type-specific epigenetic signatures. In the present study, we used stage-specific, epigenetic "fingerprints" to deduce key transcriptional regulators of the human monocytic differentiation process. We globally mapped the distribution of epigenetic enhancer marks (histone H3 lysine 4 monomethylation, histone H3 lysine 27 acetylation, and the histone variant H2AZ), describe general properties of marked regions, and show that cell type-specific epigenetic "fingerprints" are correlated with specific, de novo-derived motif signatures at all of the differentiation stages studied (ie, hematopoietic stem cells, monocytes, and macrophages). We validated the novel, de novo-derived, macrophage-specific enhancer signature, which included ETS, CEBP, bZIP, EGR, E-Box and NF-B motifs, by ChIP sequencing for a subset of motif corresponding transcription factors (PU.1, C/EBP␤, and EGR2), confirming their association with differentiationassociated epigenetic changes. We describe herein the dynamic enhancer landscape of human macrophage differentiation, highlight the power of genome-wide epigenetic profiling studies to reveal novel functional insights, and provide a unique resource for macrophage biologists. IntroductionHuman monocyte-to-macrophage differentiation is a process involving marked morphologic, functional, and transcriptional changes that proceed in the absence of proliferation. The mechanisms controlling this transition are not well understood on the molecular level, in part because both human monocytes and macrophages are hard to manipulate without triggering defense programs that interfere with normal differentiation.Recent global epigenetic and transcription factor profiling studies in various cell types have provided ample evidence for a tight relationship between transcription factor binding and the local deposition/removal of some epigenetic marks, including histone methylation or acetylation, the appearance of histone variants, or DNA demethylation. 1 Cell type-specific epigenetic signatures are particularly evident at promoter-distal sites, where histone H3K4 monomethylation/dimethylation, 2,3 histone H3K27 acetylation, 3,4 the histone variant H2AZ, 2 or DNA demethylation 5,6 indicate the presence of poised or activated lineage-specific enhancer elements. These distal regulatory elements are often cell type-specific, are correlated with gene expression, and are bound by combinations of common and cell type-specific key regulators. 1,7 For example, in the murine hematopoietic system, macrophage-specific putative enhancer elements are characterized by PU.1, C/EBP␣/␤, and AP-1 binding, whereas putative enhancer elements in a related blood-cell type (murine B cells) that are also characterized by PU.1 binding associate with a distinct set of B cell-specific factors, including E2A, EBF, and OCT2. 8 Observations of correlating transcription factor binding and epigenetic patterns were also made in other cellul...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

Pham

Benner

Lichtinger

et al. 2012

Blood

127

161

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“…Furthermore, IRF-7 was initially discovered for its ability to repress the Q promoter of the EBV-encoded EBNA genes but can effectively activate IFNA and IFNB genes (28). Finally, IRF-8 acts as an activator upon binding to PU.1 (53)(54)(55)(56)(57), yet in association with another member of the ETS family, Tel, it acts as a strong repressor of promoters containing ISRE sites (58). The molecular mechanism by which IRF-5 suppresses IRF-7 activation of the IFNA1 promoter is not yet clearly established.…”

Section: Discussionmentioning

confidence: 99%

Virus-induced Heterodimer Formation betweenIRF-5 and IRF-7 Modulates Assembly of theIFNA Enhanceosome in Vivo and Transcriptional Activity of IFNA Genes

Barnes

Field

Pitha-Rowe

2003

Journal of Biological Chemistry

107

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Type I interferons (IFN)1 play an essential role in the innate immune response against virus infection (1). In uninfected cells, the expression of IFN genes is tightly regulated. Virus infection activates transcription of type I IFN genes, and the cis-acting virus-responsive elements (VRE), located within the 110 nucleotides 5Ј of the transcription initiation site, are sufficient for virus-mediated activation (2, 3). The VRE of IFNA genes contain purine-rich GAAANN motifs that constitute the specific binding sites (IRF-E and PRDI/III) for the proteins of the interferon regulatory factor (IRF) family, whereas the VRE in the promoter of the IFNB gene contain not only PRDI/ PRDIII elements but also an NF-B (PRDII)-binding site (4).Nine cellular IRF and three viral homologues (vIRF) have been identified (4 -9). All of the cellular IRF share a region of homology in the amino terminus encompassing a highly conserved DNA binding domain (DBD) that is characterized by five tryptophan repeats (4). Three of the repeats contact DNA recognizing the GAAA or AANNGAAA sequences (10 -12). KSHV-encoded IRF that contain an imperfect DNA binding domain are not able to bind DNA with the same specificity as cellular IRF.Several of the cellular IRF were implicated in the regulation of type I IFN gene expression in virus-infected cells. IRF-1 was first identified as an activator of the IFNB gene, whereas IRF-2 antagonized the IRF-1-mediated activation and acted as a suppressor (13-15). Whereas the infected embryonic fibroblasts from IRF-1 Ϫ/Ϫ mice expressed normal levels of IFNA and -B (16, 17), it was observed that IRF-1 associates with the VRE of both human IFNA and IFNB promoters in vivo, thus suggesting that IRF-1 may contribute to the transcriptional regulation of the human IFNA genes (18,19). Three members of the IRF family (IRF-3, IRF-5, and IRF-7) were shown to be direct transducers of virus-mediated signaling and to play a crucial role in the expression of type I IFN genes (19 -26). Whereas IRF-3 is constitutively expressed in all cell types (27), constitutive expression of IRF-7 was observed only in lymphoid cells but could be induced by type I IFN in other cell types (20,28). Expression of IRF-5 was detected primarily in B cells and dendritic cells and was further enhanced by type I IFN (5, 9, 21).In the murine system, induction of type I IFN genes in virus-infected primary embryonic fibroblasts was proposed to proceed by two sequential phases. During the initial phase, which does not require protein synthesis, transcription of IFNB and IFNA4 genes was activated. The second phase, during which the rest of the IFNA subtypes were induced, depended on the IFN-mediated induction of IRF-7 expression (23, 29). However, in recently generated mice with a homozygous deletion of the IRF-7 gene, production of IFN␣ in the isolated mouse embryo fibroblasts was completely abolished, whereas the expression of IFN␤ was significantly reduced (30). These results are consistent with the observations in human cells, where expression of IRF-3 co...

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“…PU.1 also binds to IRF4, a factor structurally similar to IRF8 (24)(25)(26). IRF8, IRF1, and PU.1 are assembled together on some promoters in activated macrophages (18,(27)(28)(29)(30)(31).…”

Section: Together Irf8 -Chromatin Interaction Is Dynamic In Live Macmentioning

confidence: 99%

Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages

Laricchia-Robbio

Tamura

Karpova

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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IFN regulatory factor (IRF) 8 is a transcription factor that directs macrophage differentiation. By fluorescence recovery after photobleaching, we visualized the movement of IRF8-GFP in differentiating macrophages. Recovery data fitted to mathematical models revealed two binding states for IRF8. The majority of IRF8 was highly mobile and transiently interacted with chromatin, whereas a small fraction of IRF8 bound to chromatin more stably. IRF8 mutants that did not stimulate macrophage differentiation showed a faster recovery, revealing little interaction with chromatin. A macrophage activation signal by IFN-␥͞LPS led to a global slowdown of IRF8 movement, leading to increased chromatin binding. In fibroblasts where IRF8 has no known function, WT IRF8 moved as fast as the mutants, indicating that IRF8 does not interact with chromatin in these cells. However, upon introduction of IRF8 binding partners, PU.1 and͞or IRF1, the mobility of IRF8 was markedly reduced, producing a more stably bound component. Together, IRF8 -chromatin interaction is dynamic in live macrophages and influenced by partner proteins and immunological stimuli.real-time mobility ͉ transcription factor ͉ fluorescence recovery after photobleaching G ene expression in immune cells is controlled by binding of transcription factors to chromatin targets. A classic view is that active transcription factors stably bind to the chromatinized promoter to drive transcription, a view mostly derived from biochemical studies in vitro. With the advent of live cell technologies, the views on the behavior of transcription factors are changing. Studies by fluorescence recovery after photobleaching (FRAP) of many nuclear proteins show that they are highly mobile and only transiently interact with chromatin (1, 2). Proteins showing rapid mobility include general transcription factors, chromatin modifiers, and DNA replication factors (3-9). Some DNA-specific transcription factors, such as nuclear hormone receptors, are also highly mobile in live nuclei (10-12). In addition, Stat1 (signal transducer and activator of transcription 1), a transcription factor that regulates IFN responses, is shown to be mobile before and after translocation into the nucleus (13), although E2F and retinoblastoma protein appear to be more stationary (14). In contrast, core histones, stable components of chromatin, are essentially immobile, showing little recovery after photobleaching (15). A consensus emerging from these studies is that FRAP recovery primarily reflects interactions of nuclear proteins with chromatin and the surrounding genomic DNA (hereafter referred to as chromatin) (16). Nevertheless, photobleaching technologies are still in their early phase of application, and mechanisms regulating FRAP mobility are not fully understood. FRAP mobility might reflect an intrinsic chromatin-binding property of a protein. However, the mobility may be influenced by other factors, such as soluble molecular constituents and structural components of the nucleus. In addition, most transcripti...

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Cited by 99 publications

References 43 publications

Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

Virus-induced Heterodimer Formation betweenIRF-5 and IRF-7 Modulates Assembly of theIFNA Enhanceosome in Vivo and Transcriptional Activity of IFNA Genes

Partner-regulated interaction of IFN regulatory factor 8 with chromatin visualized in live macrophages

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