Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10

Tausendschön, Michaela; Rehli, Michael; Dehne, Nathalie; Schmidl, Christian; Döring, Claudia; Hansmann, Martin‐Leo; Brüne, Bernhard

doi:10.1016/j.bbagrm.2014.10.006

Cited by 35 publications

(48 citation statements)

References 67 publications

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“…In MDMs exposed to hypoxia (for 4–8 h) DHS F7 represents the strongest ChIP-seq signal specific for HIF1a and HIF2a [103] (Figure S10). F7 association with STAT1 was also noted after stimulation with LPS, as well as possible binding of IRF1 in response to IFN-g priming and further activation with LPS [99] (Figure S10).…”

Section: Resultsmentioning

confidence: 99%

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Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C/ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit (RelA) regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression.

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Section: Resultsmentioning

confidence: 99%

“…ChIP-seq data in response to hypoxia suggested both HIFas may bind NRAMP1 promoter, while IL-10 pre-treatment seemed to reduce HIFas binding [103] (Figure S10). It will be interesting to detail the interplay of hypoxia, infection and HIF-associated factors in regulating NRAMP1 expression.…”

Section: Resultsmentioning

confidence: 99%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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“…13 The expression of the hypoxia-inducible Adm (Adrenomedullin) gene in ISAM kidneys was significantly reduced by the weekly C.E.R.A. administration, 12 indicating that the hypoxic milieu of the ISAM kidneys was ameliorated. Analyses of tissue sections from the ISAM-REC kidneys also demonstrated that the increased expression of EpoGFP in the REP cells of ISAM disappeared after the weekly C.E.R.A.…”

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confidence: 99%

Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Suzuki

Sasaki²,

Kato

et al. 2016

Haematologica

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“…ChIP experiments coupled with sequencing showed HIF-1 and HIF-2 binding to the CTSB gene, visualized by the human genome browser (Fig. 3C) (19). Data were confirmed by ChIP, with subsequent qPCR analysis performed after 4 h of incubation under hypoxia (Fig.…”

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confidence: 82%

Inactivation of Tristetraprolin in Chronic Hypoxia Provokes the Expression of Cathepsin B

Fuhrmann

Tausendschön

Wittig

et al. 2015

Molecular and Cellular Biology

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bMacrophages play important roles in many diseases and are frequently found in hypoxic areas. A chronic hypoxic microenvironment alters global cellular protein expression, but molecular details remain poorly understood. Although hypoxiainducible factor (HIF) is an established transcription factor allowing adaption to acute hypoxia, responses to chronic hypoxia are more complex. Based on a two-dimensional differential gel electrophoresis (2D-DIGE) approach, we aimed to identify proteins that are exclusively expressed under chronic but not acute hypoxia (1% O 2 ). One of the identified proteins was cathepsin B (CTSB), and a knockdown of either HIF-1␣ or -2␣ in primary human macrophages pointed to an HIF-2␣ dependency. Although chromatin immunoprecipitation (ChIP) experiments confirmed HIF-2 binding to a CTSB enhancer in acute hypoxia, an increase of CTSB mRNA was evident only under chronic hypoxia. Along those lines, CTSB mRNA stability increased at 48 h but not at 8 h of hypoxia. However, RNA stability at 8 h of hypoxia was enhanced by a knockdown of tristetraprolin (TTP). Inactivation of TTP under prolonged hypoxia was facilitated by c-Jun N-terminal kinase (JNK), and inhibition of this kinase lowered CTSB mRNA levels and stability. We postulate a TTP-dependent mechanism to explain delayed expression of CTSB under chronic hypoxia.C hronic diseases such as diabetes, atherosclerosis, and cancer are characterized by hypoxic areas resulting, for example, from compromised perfusion of narrowed or leaky vessels. Cells of the immune system are involved in the outcome of these diseases. As part of the innate immune system, macrophages actively regulate inflammation but also the resolution of inflammation as well as tissue regeneration and remodeling. Macrophages invade hypoxic areas attracted by a number of cytokines produced by hypoxic cells. To survive and operate in a hypoxic environment, cells need a variety of adaptive mechanisms (1, 2).Hypoxia-inducible factors (HIFs) are important to coordinate hypoxic responses and consist of a constitutively expressed ␤-subunit and an oxygen-regulated ␣-subunit. Both are members of the helix-loop-helix/Per, ARNT, and SIM (PAS) transcription factor family (1, 3). Among the ␣-subunits, HIF-1␣ and HIF-2␣ are best characterized. Both contain an oxygen-dependent degradation domain (ODD) with two conserved prolyl residues that are hydroxylated by prolyl hydroxylases (PHDs) 1 to 3 when sufficient oxygen is available, allowing their proteasomal degradation (4, 5). PHDs are impaired under hypoxia, which in turn causes accumulation and translocation of HIF-␣ into the nucleus. The ␣-subunit forms a heterodimer with the ␤-subunit and binds to hypoxiaresponsive elements (HRE) in regulatory regions of target genes (6). By recruiting cofactors like p300 or CBP, the HIF proteins enhance transcription of about 400 target genes (7,8). Although HIF abundance is mostly regulated by protein stability, regulation of HIF-1␣ mRNA via binding of tristetraprolin (TTP) to AU-rich elements (AREs) in the 3...

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Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10

Cited by 35 publications

References 67 publications

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Inactivation of Tristetraprolin in Chronic Hypoxia Provokes the Expression of Cathepsin B

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