Destruction of a distal hypoxia response element abolishes<i>trans</i>-activation of the<i>PAG1</i>gene mediated by HIF-independent chromatin looping

Schörg, Alexandra; Santambrogio, Sara; Platt, James L.; Schödel, Johannes; Lindenmeyer, Maja T.; Cohen, Clemens D.; Schrödter, Katrin; Mole, David R.; Wenger, Roland H.; Hoogewijs, David

doi:10.1093/nar/gkv506

Cited by 27 publications

(30 citation statements)

References 53 publications

(76 reference statements)

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“…Transcript levels were calculated by comparison with a calibrated standard and expressed as ratios relative to ribosomal protein L28 mRNA levels. Immunoblotting, signal imaging and quantification were performed as previously reported [ 64 ]. Values were normalized to a β-actin loading control.…”

Section: Methodsmentioning

confidence: 99%

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Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

et al. 2016

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The involvement of estrogen (E2) and hypoxia in tumor progression is well established. Hypoxia has been reported to activate and degrade estrogen receptor alpha (ERα) in breast cancer cells. Furthermore, E2 has been shown to regulate hypoxia-inducible factor (HIF)-1α protein, but its role in HIF-2α regulation remains largely unexplored. In this study, we found that both HIF-2α mRNA and protein were down-regulated in ER positive but not ER negative breast cancer cells upon treatment with E2. The analysis of 690 samples derived from 608 mixed and 82 triple-negative breast cancer patients revealed that high nuclear HIF-2α tumor levels are associated with a worse prognosis specifically in human epidermal growth factor receptor 2 (HER2) and hormone receptor positive patients. Consistently, ERα/HER2 positive breast cancer cells displayed less pronounced downregulation of HIF-2α by E2. Experiments using a histone deacetylase inhibitor indicate that the E2 mediated decrease in HIF-2α mRNA is due to transcriptional repression. A functional estrogen response element (ERE) was identified in the first intron of the gene encoding HIF-2α (EPAS1), suggesting transcriptional co-repressor recruitment by ERα. Our results demonstrate a novel modulation of HIF-2α in breast cancer cells, explaining the opposing regulation between HIF-1α and HIF-2α in hormone-responsive breast cancer.

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Section: Methodsmentioning

confidence: 99%

“…Human GATA-2, GATA-3, and GATA-4 cloned into pcDNA3.1 were kindly provided by C. Dame (Berlin, Germany). Dual luciferase reporter gene assays were performed as described previously [ 64 ].…”

Section: Methodsmentioning

confidence: 99%

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

et al. 2016

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“…Specifically, upon truncation of E2-3, the truncated E2-3 still interacted with the promoters of IFITM1, 2 and 3. A recent paper about a distal enhancer regulating PAG1 gene also reported a similar phenomenon [46]. It's possible that the driving force looping E2-3 to IFITM gene cluster might not be disrupted upon truncation of E2-3, suggesting roles of architectural factors residing outside E2-3, possibly CTCF and cohesin [47].…”

Section: Discussionmentioning

confidence: 79%

Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin interactions

Shi

Shen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Interferon-induced transmembrane protein (IFITM) 1, 2 and 3 genes encode a family of interferon (IFN)-induced transmembrane proteins that block entry of a broad spectrum of pathogens. However, the transcriptional regulation of these genes, especially whether there exist any enhancers and their roles during the IFN induction process remain elusive. Here, through public data mining, episomal luciferase reporter assay and in vivo CRISPR-Cas9 genome editing, we identified an IFN-responsive enhancer located 35kb upstream of IFITM3 gene promoter upregulating the IFN-induced expression of IFITM1, 2 and 3 genes. Chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA) and luciferase reporter assay demonstrated that signal transducers and activators of transcription (STAT) 1 bound to the enhancer with the treatment of IFN and was indispensable for the enhancer activity. Furthermore, using chromosome conformation capture technique, we revealed that the IFITM1, 2 and 3 genes physically clustered together and constitutively looped to the distal enhancer through long-range interactions in both HEK293 and A549 cells, providing structural basis for coordinated regulation of IFITM1, 2 and 3 by the enhancer. Finally, we showed that in vivo truncation of the enhancer impaired IFN-induced resistance to influenza A virus (IAV) infection. These findings expand our understanding of the mechanisms underlying the transcriptional regulation of IFITM1, 2 and 3 expression and its ability to mediate IFN signaling.

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“…Tests of association with hypoxia‐inducible transcripts, such as gene set enrichment analyses (GSEA), have demonstrated clear statistical association with positive effects on gene expression, suggesting that at least some of these loci are hypoxia‐inducible transcriptional enhancers . However, with the exception of a small number of loci , physical association with a hypoxia‐inducible promoter has not been defined. Nor is it known whether any such associations are induced following exposure of cells to hypoxia and/or the binding of HIF to DNA or whether they are present prior to the induction of HIF and contribute to the cell‐type‐specific operation of the HIF transcriptional response.…”

Section: Introductionmentioning

confidence: 99%

Capture‐C reveals preformed chromatin interactions between HIF ‐binding sites and distant promoters

et al. 2016

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Hypoxia‐inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia. Pan‐genomic analyses, using chromatin immunoprecipitation and transcript profiling, have revealed large numbers of HIF‐binding sites that are generally associated with hypoxia‐inducible transcripts, even over long chromosomal distances. However, these studies do not define the specific targets of HIF‐binding sites and do not reveal how induction of HIF affects chromatin conformation over distantly connected functional elements. To address these questions, we deployed a recently developed chromosome conformation assay that enables simultaneous high‐resolution analyses from multiple viewpoints. These assays defined specific long‐range interactions between intergenic HIF‐binding regions and one or more promoters of hypoxia‐inducible genes, revealing the existence of multiple enhancer–promoter, promoter–enhancer, and enhancer–enhancer interactions. However, neither short‐term activation of HIF by hypoxia, nor long‐term stabilization of HIF in von Hippel–Lindau (VHL)‐defective cells greatly alters these interactions, indicating that at least under these conditions, HIF can operate on preexisting patterns of chromatin–chromatin interactions that define potential transcriptional targets and permit rapid gene activation by hypoxic stress.

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Destruction of a distal hypoxia response element abolishestrans-activation of thePAG1gene mediated by HIF-independent chromatin looping

Cited by 27 publications

References 53 publications

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin interactions

Capture‐C reveals preformed chromatin interactions between HIF ‐binding sites and distant promoters

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