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Multi-dimensional histone modifications for coordinated regulation of gene expression under hypoxia or clioquinol (CQ) treatment [gene expression]

ABSTRACT: Clioquinol (CQ) has been identified as a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1a specific asparaginyl hypoxylase (Factor inhibiting HIF-1, FIH-1). We previously showed that hypoxia coordinately regulate induction or repression of hypoxia-responsive genes by altering different types of methylations (H3K4me3, H3K9me3, and H3K27me3) at gene level. Here, we investigated CQ-mediated regulation of the expression of hypoxia-responsive genes and whether CQ had a similar effect on histone methylation and transcription of target genes under hypoxia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176557 | GEO | 2022/05/25

REPOSITORIES: GEO

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Multi-dimensional histone modifications for coordinated regulation of gene expression under hypoxia or clioquinol (CQ) treatment.

Project description:Clioquinol (CQ) has been identified as a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1a specific asparaginyl hypoxylase (Factor inhibiting HIF-1, FIH-1). We previously showed that hypoxia coordinately regulate induction or repression of hypoxia-responsive genes by altering different types of methylations (H3K4me3, H3K9me3, and H3K27me3) at gene level. Here, we investigated CQ-mediated regulation of the three histone methylations and whether CQ had a similar effect on histone methylation and transcription of target genes under hypoxia.

2022-05-25 | GSE176379 | GEO

Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition:Sequencing Data

Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an /-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIF levels and FIH catalysis regulates HIF activity. How differences in HIF hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

2016-10-25 | E-MTAB-4264 | biostudies-arrayexpress

Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition: Microarray data

Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an Î±/Î²-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIFÎ± levels and FIH catalysis regulates HIF activity. How differences in HIFÎ± hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

2016-08-31 | E-MTAB-4300 | biostudies-arrayexpress

The Factor Inhibiting HIF regulates T cell differentiation and anti-tumor efficacy

Project description:T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumor suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion in vivo, and improves anti-tumor activity in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy.

2023-06-14 | GSE234381 | GEO

SH-SY5Y cells: DMSO vs. clioquinol

Project description:Transcriptional profiling of human SH-SY5Y neuroblastoma cells comparing DMSO-treated control cells with those treated with 50 microM clioquinol (CQ) for 24 h. Two-condition experiment, DMSO vs. CQ . Biological replicates: 1DMSO, 1 CQ. One replicate per array.

2012-10-01 | E-GEOD-32173 | biostudies-arrayexpress

SH-SY5Y cells: DMSO vs. clioquinol

Project description:Transcriptional profiling of human SH-SY5Y neuroblastoma cells comparing DMSO-treated control cells with those treated with 50 microM clioquinol (CQ) for 24 h.

2012-10-01 | GSE32173 | GEO

Factor Inhibiting HIF catalyses two asparaginyl-hydroxylations in VNVN motifs of ankyrin proteins

Project description:The aspariginyl-hydroxylase activity of Factor Inhibiting HIF (FIH) is a key regulator of the transcriptional activity of the hypoxia inducible factor. FIH also catalyses the hydroxylation of asparaginyl- and other-residues in ankyrin repeat domain (ARD) containing proteins, including Apoptosis stimulating of p53 (ASPP) protein family members. ASPP2 is reported to undergo a single FIH catalysed hydroxylation at Asn-986. We report biochemical and crystallographic evidence showing FIH can catalyse the unprecedented post-translational hydroxylation of both asparaginyl-residues in “VNVN” and related motifs of ankyrin repeat domains in apoptosis-stimulating of p53 (ASPP) proteins (i.e. ASPP1, ASPP2 and iASPP) and the related ASB11 and p18-INK4C proteins. The results extend the substrate scope of FIH catalysis and may have implications for its role in the hypoxic response and, ASPP protein function.

2022-08-11 | PXD017278 | Pride

Determining the hydroxylation status of NAA10-Trp38

Project description:NAA10 is the major human N-terminal acetyltransferase (NAT). The KAT activity of NAA10 towards hypoxia-inducible factor 1α (HIF-1α) was recently reported to depend on the hydroxylation at Trp38 of NAA10 by factor inhibiting HIF-1α (FIH). As a consequence, Trp38 hydroxylation status was proposed to act as a general NAA10-switch between its NAT and KAT state. We attempted to quantify the degree of hydroxylation of NAA10. We could not detect any hydroxylation of Trp38 of NAA10 in several human cell lines.

2022-02-16 | PXD023655 | Pride

Expression data of Saccharomyces cerevisiae treated with clioquinol

Project description:Clioquinol (CQ or iodochlorhydroxyquin, 5-chloro-7-iodo-8-hydroxyquinoline) is a hydrophobic chelator of copper, zinc, and iron. It was extensively used as an antibiotic for the treatment of diarrhea and skin infection in the mid-1900s, but then withdrawn because it was reported to be associated with subacute myelo-optic neuropathy (SMON) in Japan. Interest in this drug was recently revived as it was shown that CQ specifically kills cancer cells and significantly decreases Abeta level. Nevertheless, the underlying mechanisms of CQ drug effects and side effects are still unclear. We used yeast, Saccharomyces cerevisiae, as a model to study how CQ affects molecular and cellular functions. Genechip analysis was utilized to examine the effect of CQ on gene expression at the genomic level. To study gene expression profiles of yeast treated with CQ, yeast cells were treated with CQ or DMSO for 5 hours and RNAs were extracted for microarray analysis.

2010-06-08 | E-GEOD-17257 | biostudies-arrayexpress

Expression data of Saccharomyces cerevisiae treated with clioquinol

Project description:Clioquinol (CQ or iodochlorhydroxyquin, 5-chloro-7-iodo-8-hydroxyquinoline) is a hydrophobic chelator of copper, zinc, and iron. It was extensively used as an antibiotic for the treatment of diarrhea and skin infection in the mid-1900s, but then withdrawn because it was reported to be associated with subacute myelo-optic neuropathy (SMON) in Japan. Interest in this drug was recently revived as it was shown that CQ specifically kills cancer cells and significantly decreases Aβ level. Nevertheless, the underlying mechanisms of CQ’s drug effects and side effects are still unclear. We used yeast, Saccharomyces cerevisiae, as a model to study how CQ affects molecular and cellular functions. Genechip analysis was utilized to examine the effect of CQ on gene expression at the genomic level.

2010-05-21 | GSE17257 | GEO

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