Modifying Gene Expression Programs by Altering Core Promoter Chromatin Architecture

Lomvardas, Stavros; Thanos, Dimitris

doi:10.1016/s0092-8674(02)00822-x

Cited by 172 publications

(152 citation statements)

References 32 publications

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“…Because studies of transcription factor function have largely been restricted to a select set of promoters identified by changes in gene expression, very little is known about transcription factors binding to regions without a direct transcriptional effect. It is well known that some genes are regulated by combinatorial action; general or tissue-specific factors contribute architectures conducive to the functions of an inducible protein (46,52,68). This leaves open the possibility of the inverse situation, where inducible transcription factors bind to any number of promoters lacking the accessory factors necessary for a transcriptional response.…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.The tumor microenvironment is a major factor influencing tumor growth, metastatic potential, and response to chemotherapeutic drugs and radiation therapy (7). The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of key enzymes in anaerobic glycolysis and proangiogenic factors (i.e., vascular endothelial growth factor), aiding cells in adapting to a low-oxygen environment (15). Thus, a tumor adapts to hypoxia first by sustaining itself via anaerobic metabolism and then by stimulating angiogenesis to acquire more nutrients and oxygen. However, the resulting vasculature tends to have aberrant structures with irregular blood flow and leaky walls, paradoxically creating regions of transient hypoxia and reoxygenation (76). Reoxygenation after hypoxia causes DNA damage, exacerbating genomic instability (25). The porous structure of the tumor vasculature may also provide an escape route for metastasizing cells. Repeated cycles of hypoxia, vascular formation, and reoxygenation select for cells that are more likely to survive in a restrictive environment. The consequences of this process are cancer cells that are more aggressive, more likely to metastasize, and more likely to be resistant to radiation and chemotherapy. Intimately tied to this process is the selection for cells that have lost the expression of functional p53 (19).A variety of cellular stresses, including DNA damage, oncogenic transformation, and hypoxia, stabilize the p53 protein by activating a host of stress-inducible kinases that phosphorylate p53 and MDM2, resulting in increased levels of p53 (17). Stabilized ...

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Section: Discussionmentioning

confidence: 99%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

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“…Recently it has been shown that nucleosomes positioned across the transcriptional control regions of different genes, including IL-12p35 (61), IL-12p40 (62,63), IL-2 (64), IFN␤ (42,65), and HIV-1 long terminal repeat (66), are remodeled upon cell activation. Together with TNFSF6, these genes share a common low (or undetectable) basal transcription rate coupled to a high transcription rate in response to activating factors.…”

Section: Discussionmentioning

confidence: 99%

Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Castellano

Vire

Pion

et al. 2006

Journal of Biological Chemistry

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Fas ligand (FasL/CD95L/TNFSF6), a member of the tumor necrosis factor family, initiates apoptosis in lymphoid and nonlymphoid tissues by binding to its receptor Fas (CD95/TNFRSF6). Although the transcriptional control of TNFSF6 gene expression is subjected to intense study, the role of its chromatin organization and accessibility to the transcriptional machinery is not known. Here, we determined the chromatin organization of TNFSF6 gene 5 regulatory regions. Using the indirect end-labeling technique, a unique region named HSS1 and encompassing nucleotides ؊189 to ؉185 according to the transcriptional start site, was identified throughout a 20-kilobase nucleosomal DNA domain surrounding the promoter. The HSS1 region displayed hypersensitivity to in vivo DNase I digestion in TNFSF6-expressing cells only, including upon T cell activation. Hypersensitivity to micrococcal nuclease digestion and to specific restriction enzyme digestion suggested the precise positioning of two nucleosomes across the transcription start site and minimal promoter region, likely interfering with TNFSF6 active transcription in T lymphocytes. Indeed, HSS1 hypersensitivity to nuclease digestion strictly correlated with TNFSF6 transcription, including in primary and leukemia T cells. HSS1 chromatin remodeling preceded detectable TNFSF6 mRNA accumulation and was blocked by cycloheximide that also prevented TNFSF6 transcription. However, DNA methylation levels of the TNFSF6 HSS1 region did not correlate with transcriptional activation. Induction of global protein acetylation by treatment with histone deacetylase inhibitors was not accompanied by HSS1 chromatin remodeling and/or TNFSF6 transcription. We conclude that chromatin remodeling is a primary event in the activation of TNFSF6 expression in primary and leukemia T cells and that mechanisms independent of protein deacetylation and of DNA methylation of the TNFSF6 promoter region are involved in the repression of TNFSF6 gene expression.The TNFSF family related members are type II transmembrane proteins. Besides of their role in many important biological processes such as development, organogenesis, immunity, cell death, and survival, TNFSFs are implicated in various acquired or genetic human diseases ranging from septic shock to autoimmune disorders, allograft rejection, viral infections, and cancer (1). Hence, various therapeutic approaches aim to target these molecules, and there has been much interest toward the elucidation of the molecular mechanisms controlling their expression. TNFSF family member expression is contextually dependent on the nature, differentiation, activation, and cell cycle status of producing tissues. The regulated expression of the TNFSF genes implicates not only transcriptional but also post-transcriptional and post-translational mechanisms, together ensuring appropriate spatiotemporal expression. Escape of this tightly controlled expression has been described in various pathological conditions, including viral infections or neoplasm.TNFSF6 (FasL/CD95L) is a key pl...

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“…Fixed cells were used at a concentration of 2 ϫ 10 7 cells per experimental point. ChIP assays were performed as described (38). For each immunoprecipitation, 10 g of chromatin was used.…”

Section: Cd25mentioning

confidence: 99%

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes

Panagoulias

Georgakopoulos

Αγγελετοπούλου

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldIL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions.

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Modifying Gene Expression Programs by Altering Core Promoter Chromatin Architecture

Cited by 172 publications

References 32 publications

Functional Analysis of p53 Binding under Differential Stresses

Functional Analysis of p53 Binding under Differential Stresses

Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes

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