Correction: Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm

Li, Xiaoyong; MacArthur, Stewart; Bourgon, Richard; Nix, David A.; Pollard, Daniel A.; Iyer, Venky N.; Hechmer, Aaron; Simirenko, Lisa; Stapleton, Mark; Hendriks, Cris L. Luengo; Chu, Hou Cheng; Ogawa, Norio; Inwood, William; Sementchenko, Victor; Beaton, Amy; Weiszmann, Richard; Celniker, S; Knowles, David; Gingeras, T; Speed, Terence P.; Biggin, Mark D.

doi:10.1371/journal.pbio.0060190

Cited by 8 publications

(4 citation statements)

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“…1A shows a schematic representation; see Table S1 in the supplemental material for complete tabulated results). A common phenomenon with genome-wide ChIP experiments is nonfunctional binding, where a transcription factor is shown to bind but fails to regulate nearby genes (29). Even though our initial filter comparing VHL-repressed expression to HIF binding would be expected to select functional HIF targets, VHL has also been shown to regulate several cellular processes independently of HIF (4,49).…”

Section: Resultsmentioning

confidence: 99%

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Krieg

Rankin

Chan

et al. 2010

Molecular and Cellular Biology

310

316

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The hypoxia-inducible transcription factors (HIFs) directly and indirectly mediate cellular adaptation to reduced oxygen tensions. Recent studies have shown that the histone demethylase genes JMJD1A, JMJD2B, and JARID1B are HIF targets, suggesting that HIFs indirectly influence gene expression at the level of histone methylation under hypoxia. In this study, we identify a subset of hypoxia-inducible genes that are dependent on JMJD1A in both renal cell and colon carcinoma cell lines. JMJD1A regulates the expression of adrenomedullin (ADM) and growth and differentiation factor 15 (GDF15) under hypoxia by decreasing promoter histone methylation. In addition, we demonstrate that loss of JMJD1A is sufficient to reduce tumor growth in vivo, demonstrating that histone demethylation plays a significant role in modulating growth within the tumor microenvironment. Thus, hypoxic regulation of JMJD1A acts as a signal amplifier to facilitate hypoxic gene expression, ultimately enhancing tumor growth.Cellular hypoxia occurs when the demands of growth and metabolism of a tissue surpass the vascular oxygen supply. In response to hypoxia, cells undergo specific alterations in gene expression patterns geared to promote cell survival and maintain homeostasis. This response not only is important in normal development but also is a critical part in the progression of cancers (7). Hypoxia has been implicated in activating the metabolic shift to anaerobic glycolysis, promoting the epithelial-to-mesenchymal transition (EMT), inducing the secretion of proangiogenic factors, and remodeling the extracellular matrix. Although several transcription programs are activated in response to hypoxia, the hypoxia-inducible factors (HIFs) regulate a critical repertoire of genes, making them central regulators of the cellular response to hypoxia (10, 34).The HIFs are heterodimeric transcription factors consisting of an oxygen-sensitive alpha subunit (HIF-1␣, HIF-2␣, or HIF-3␣) and a constitutively expressed HIF-1␤ subunit (also known as the arylhydrocarbon nuclear translocator [ARNT]). Under conditions where oxygen concentration is not limiting, HIF-␣ subunits are hydroxylated by prolyl-hydroxylases, targeting them for ubiquitin-mediated degradation by the von Hippel-Lindau tumor suppressor (VHL) (18,19). Under hypoxic conditions, HIF-␣ protein is stabilized, translocates to the nucleus, dimerizes with ARNT, and binds hypoxia-responsive elements (HREs) in the regulatory regions of target genes (51). HIF-1␣ and HIF-2␣ will bind the same sequences in cells but do not have completely overlapping abilities to regulate genes (5, 17, 44). Under certain conditions, HIF-3␣ functions as a dominant negative, antagonizing the activity of HIF-1 and HIF-2 (32).Several hundred genes are induced in response to hypoxia, and a great deal of research has been focused on identifying direct HIF target genes (34). The massive transcriptional reorganization mediated by hypoxia and HIFs suggests that changes in histone modification would create epigenetic reinforcement o...

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Section: Resultsmentioning

confidence: 99%

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Krieg

Rankin

Chan

et al. 2010

Molecular and Cellular Biology

310

316

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“…Recent studies of Drosophila embryos suggest that in general, transcription factors bind thousands of active and inactive regions of the chromosome, but functional interactions in vivo are ultimately governed by higher-order rules (33). Others have also suggested that only a small subset of predicted transcription factor binding sequences are functional in vivo (6).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Translocated Ehrlichia chaffeensis Ankyrin Protein Interacts with a Specific Adenine-Rich Motif of Host Promoter and Intronic Alu Elements

Zhu¹,

Nethery²,

Kuriakose³

et al. 2009

Infect Immun

136

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Ehrlichiae are obligately intracellular bacteria that reside and replicate in phagocytes by circumventing host cell defenses and modulating cellular processes, including host cell gene transcription. However, the mechanisms by which ehrlichiae influence host gene transcription have largely remained undetermined. Numerous ankyrin and tandem repeat-containing proteins associated with host-pathogen interactions have been identified in Ehrlichia species, but their roles in pathobiology are unknown. In this study, we determined by confocal immunofluorescence microscopy and by immunodetection in purified nuclear extracts that the ankyrin repeat-containing protein p200 is translocated to the nuclei of Ehrlichia-infected monocytes. Chromatin immunoprecipitation (ChIP) with DNA sequencing revealed an Ehrlichia chaffeensis p200 interaction located within host promoter and intronic Alu-Sx elements, the most abundant repetitive elements in the human genome. A specific adenine-rich (mid-A-stretch) motif within Alu-Sx elements was identified using electrophoretic mobility shift and NoShift assays. Whole-genome analysis with ChIP and DNA microarray analysis (ChIP-chip) determined that genes (n ‫؍‬ 456) with promoter Alu elements primarily related to transcription, apoptosis, ATPase activity, and structural proteins associated with the nucleus and membrane-bound organelles were the primary targets of p200. Several p200 target genes (encoding tumor necrosis factor alpha, Stat1, and CD48) associated with ehrlichial pathobiology were strongly upregulated during infection, as determined by quantitative PCR. This is the first study to identify a nuclear translocation of bacterially encoded protein by E. chaffeensis and to identify a specific binding motif and genes that are primary targets of a novel molecular strategy to reprogram host cell gene expression to promote survival of the pathogen.Ehrlichia chaffeensis and Ehrlichia canis are obligately intracellular bacteria that reside and replicate within cytoplasmic vacuoles in mononuclear phagocytes. Ehrlichiae are maintained in nature by persistent infection of vertebrate hosts and are transmitted by arthropods (ticks), and thus, their existence requires adaptation to host-specific environments and evasion of both innate and adaptive immune mechanisms (48,49,53).

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“…Recent studies have also shown lack of changes of gene expression for a large fraction of genes that are bound by transcription factors when they are perturbed in loss-of-function models (33,74). This is likely to reflect redundant roles of other DNA-binding activators acting on the same genes, although some binding events could be truly nonfunctional, as recently proposed for several Drosophila regulators (32). Such findings highlight that the study of transcription factor occupancy alone is insufficient for understanding gene regulatory programs.…”

Section: Hnf1␣ Exerts Opposed Roles On Cell Growth and Oncogenesis Inmentioning

confidence: 91%

Hnf1α (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver

Servitja

Pignatelli

Maestro

et al. 2009

Molecular and Cellular Biology

122

132

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Heterozygous HNF1A mutations cause pancreatic-islet ␤-cell dysfunction and monogenic diabetes (MODY3). Hnf1␣ is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1␣ regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1␣ targets. We demonstrate that Hnf1␣ can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1␣ is essential only for the transcription of a minor fraction of its direct-target genes. Even among genes that were expressed in both liver and islets, the subset of targets showing functional dependence on Hnf1␣ was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1␤ at selected genes in Hnf1a-deficient liver. In keeping with these findings, the biological consequences of Hnf1a deficiency were markedly different in islets and liver. Notably, Hnf1a deficiency led to impaired large-T-antigen-induced growth and oncogenesis in ␤ cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1␣ governs broad, highly tissue-specific genetic programs in pancreatic islets and liver and reveal key consequences of Hnf1a deficiency relevant to the pathophysiology of monogenic diabetes.

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Correction: Transcription Factors Bind Thousands of Active and Inactive Regions in the Drosophila Blastoderm

Cited by 8 publications

References 0 publications

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Regulation of the Histone Demethylase JMJD1A by Hypoxia-Inducible Factor 1α Enhances Hypoxic Gene Expression and Tumor Growth

Nuclear Translocated Ehrlichia chaffeensis Ankyrin Protein Interacts with a Specific Adenine-Rich Motif of Host Promoter and Intronic Alu Elements

Hnf1α (MODY3) Controls Tissue-Specific Transcriptional Programs and Exerts Opposed Effects on Cell Growth in Pancreatic Islets and Liver

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