Systems Analysis of ATF3 in Stress Response and Cancer Reveals Opposing Effects on Pro-Apoptotic Genes in p53 Pathway

Tanaka, Yujiro; Nakamura, Aya; Morioka, M.; Inoue, Seijiro; Tamamori‐Adachi, Mimi; Yamada, Kazuhiko; Taketani, Kenji; Kawauchi, Junya; Tanaka-Okamoto, Miki; Miyoshi, Jun; Tanaka, Hiroshi; Kitajima, Shigetaka

doi:10.1371/journal.pone.0026848

Cited by 54 publications

(48 citation statements)

References 57 publications

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“…ATF3 is activated dramatically in various stress conditions in a variety of tissues (20,21). The ATF3 transcriptional network itself is still poorly described and may vary depending on the cellular context (22)(23)(24).…”

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confidence: 99%

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

Kristensen

Epanchintsev

Rauschendorf

et al. 2013

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

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Significance Genotoxic attack results in temporary arrest of RNA synthesis. Mutations in the DNA repair factor Cockayne syndrome B gene product (CSB) that are responsible for the Cockayne syndrome phenotype lead to clinical features such as developmental and neurodegenerative defects and photosensitivity. In UV-irradiated CSB-deficient CS1AN cells, certain genes remain permanently repressed by the activating transcription factor 3, the product of a stress-response gene, which cannot be removed from promoter by the transcription machinery. We suggest that transcriptional defects observed in UV-irradiated CSB-deficient cells result from the permanent transcriptional repression of certain genes as well as from defects in DNA repair.

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confidence: 99%

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

Kristensen

Epanchintsev

Rauschendorf

et al. 2013

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

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“…As an example, Figure 5B shows the enriched BP (false-discovery rate ≤ 10%) for ATF3 in four cell types. ATF3 is a stress-inducible TF involved in homeostasis regulating cell-cycle, apoptosis, cell adhesion, and signaling (Allen-Jennings et al 2001;Tanaka et al 2011). We found that ATF3 cofactors are enriched for cell cycle and proliferation functions in three out of four cell lines.…”

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confidence: 50%

Heterogeneity of transcription factor binding specificity models within and across cell lines

2016

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Complex gene expression patterns are mediated by the binding of transcription factors (TFs) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TF's DNA binding interaction partners, motivating genomic context-based models of TF occupancy. However, approaches thus far have assumed a uniform TF binding model to explain genome-wide cell-type-specific binding sites. Therefore, the cell type heterogeneity of TF occupancy models, as well as the extent to which binding rules underlying a TF's occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble-based approach (TRISECT) to identify the heterogeneous binding rules for cell-type-specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-seq data in four to 12 different cell types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy. Importantly, many of the binding rules derived from individual cell types are shared across cell types and reveal distinct yet functionally coherent putative target genes in different cell types. Closer inspection of the predicted cell-type-specific interaction partners provides insights into the context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising the interaction partners within a cell type, many of which nevertheless transcend cell types. Notably, the putative targets of shared binding rules in different cell types, while distinct, exhibit significant functional coherence.

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“…DNA damage followed by ATF3 induction was described by several authors [4,10,15,16]. We have demonstrated a significant increase in DNA strand breaks in the MOC model system [3].…”

Section: Discussionmentioning

confidence: 63%

“…Context-dependent ATF3 is described as a principal target of EGR1 [8] and discussed as tumour suppressor [4,12,23] and promoter [5,15] too. The same is applied for EGR1 [5,24].…”

Section: Discussionmentioning

confidence: 99%

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ATF3-Dependent Regulation of EGR1 in vitro and in vivo

Schoen

Koitzsch²

2017

ORL

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Background/Aims: Activating transcription factor 3 (ATF3) and early growth response protein 1 (EGR1) are reported to interact, but their use as prognostic factors in cancer is discussed controversially. Methods: We measured ATF3 and EGR1 gene expression changes in human mini-organ cultures (MOCs) of healthy nasal epithelia, UM-SCC-22B, and FADU_DD cells after acid reflux exposure. Next, ATF3 and EGR1 gene expression was analysed in tumour tissues and related to the median expression of autologous reference tissue samples. Results: ATF3 and EGR1 mRNA expression was significantly reduced after consecutive exposure of MOCs at pH <7.0 to artificial gastric juice (refluxate). In contrast, ATF3 mRNA was upregulated significantly within the first hour of incubation. EGR1 mRNA exhibited no significant changes. The analysed cell lines exhibited a cell line-specific alteration. In FADU_DD cells, the upregulation of EGR1 was significant after refluxate exposure, but in HN-SCC 22B, no significant changes were detected. The analysis of the HNSCC samples confirmed the heterogeneous data of the literature. Conclusion: The data maintain the hypothesis that ATF3 and EGR1 are involved in the beginning of inflammatory processes. Whether these two transcription factors act as tumour suppressors or promoters is context dependent and warrants analysis in further studies.

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Systems Analysis of ATF3 in Stress Response and Cancer Reveals Opposing Effects on Pro-Apoptotic Genes in p53 Pathway

Cited by 54 publications

References 57 publications

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress

Heterogeneity of transcription factor binding specificity models within and across cell lines

ATF3-Dependent Regulation of EGR1 in vitro and in vivo

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