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LncRNA LUCAT1 Promotes Glioblastoma Progression by Enhancing HIF1⍺ Activity [RNA-seq]

ABSTRACT: Glioblastoma (GBM) is characterized by a high degree of hypoxia. Hypoxia-inducible factors (HIFs) modulate glioma stem-like cell (GSC) responses to hypoxia and promote GBM progression, therapeutic resistance, and recurrence. Here we identify a new transcript of the long non-coding RNA LUCAT1 and show that it reinforces HIF1⍺ signaling in GSCs under hypoxia. LUCAT1 expression is highly induced under hypoxia in GBM and GSCs in a HIF1⍺-dependent manner. High LUCAT1 expression in human GBM correlates with increased aggression and poor survival. Mechanistically, LUCAT1 associates with chromatin and modulates interaction between HIF1⍺ and coactivator CBP to hypoxia response elements (HREs) to drive HIF1⍺-target gene expression under hypoxia. Thus, LUCAT1 acts as a positive feedback factor to augment HIF1⍺ signaling under hypoxic stress in GSCs. Loss of LUCAT1 reduces tumor growth and prolongs mouse survival in xenograft models of GBM. Our findings provide new insights into how GSCs regulate gene expression under hypoxia and identify LUCAT1 as therapeutic target in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255501 | GEO | 2024/03/12

REPOSITORIES: GEO

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LncRNA LUCAT1 Promotes Glioblastoma Progression by Enhancing HIF1⍺ Activity [ChIP-seq]

Project description:Glioblastoma (GBM) is characterized by a high degree of hypoxia. Hypoxia-inducible factors (HIFs) modulate glioma stem-like cell (GSC) responses to hypoxia and promote GBM progression, therapeutic resistance, and recurrence. Here we identify a new transcript of the long non-coding RNA LUCAT1 and show that it reinforces HIF1⍺ signaling in GSCs under hypoxia. LUCAT1 expression is highly induced under hypoxia in GBM and GSCs in a HIF1⍺-dependent manner. High LUCAT1 expression in human GBM correlates with increased aggression and poor survival. Mechanistically, LUCAT1 associates with chromatin and modulates interaction between HIF1⍺ and coactivator CBP to hypoxia response elements (HREs) to drive HIF1⍺-target gene expression under hypoxia. Thus, LUCAT1 acts as a positive feedback factor to augment HIF1⍺ signaling under hypoxic stress in GSCs. Loss of LUCAT1 reduces tumor growth and prolongs mouse survival in xenograft models of GBM. Our findings provide new insights into how GSCs regulate gene expression under hypoxia and identify LUCAT1 as therapeutic target in GBM.

2024-03-12 | GSE255502 | GEO

alternative promoter array HeLa HIF1 ChIP-chip

Project description:DNA binding profiling of endogenous HIF1A on proximal promoters in human HeLa cells exposed to 1% oxygen (hypoxia), using normoxic cells (21% oxygen) as reference. Biological background: The Hypoxia Inducible Factor Family of transcription factors is proposed as the main orchestrator of the cellular response to hypoxia. HIFs are heterodimers of a HIF alpha and a HIF beta subunit. HIF alpha protein stability is regulated by oxygen-dependent proteasomal degradation, and hence HIFs are strongly stabilized in hypoxia. Purpose of the study: a number of HIF1 ChIP-chip studies have been reported, employing various cell types, array platforms and HIF antibodies, and the overlap of HIF binding locations in these studies is relatively small. The aim of this study was to characterize HIF1 binding in an additional cell line (HeLa), and employing a different HIFalpha antibody. Experimental design: We conducted a total of six hybridizations employing four biological replicates. For two biological replicates, we performed dye-swap technical replicate experiments. Results summary: We identified 55 HIF binding locations in HeLa cells (FDR<2%). While this number is relatively low compared to previous studies, presumably due to limiting antibody sensitivity, the overlap with data from other cell lines is comparable to our HeLa data.

2012-05-20 | E-MEXP-3499 | biostudies-arrayexpress

Genome-wide binding sites of Hypoxia inducible factor 1 (HIF1) and histone modifications

Project description:We report the high-throughput profilings of HIF1 and histone modifications in human umbilical vein endothelial cells (HUVEC). By obtaining over two billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of HUVEC under normoxia and hypoxia. We find that HIF1binds to not only to transcriptional starting sites but also enhancer regions and that HIF1 binding sites were overlapped with lysine 4 trimethylatio, monomethylation and lysine 27 acetylation . Finally, we show that chromatin state can change under hypoxia by using chromatin conformational capture assay. This study provides novel insights into the interaction between HIF1 and KDM3A and also the epigenetic regulation of HIF1. Examination of HIF1 and 3 different histone modifications in HUVEC under 2 conditions. Related gene expression data is provided in GSE35932.

2012-07-12 | E-GEOD-39089 | biostudies-arrayexpress

HIF1/2-exerted control over glycolysis but not OxPHOS pathways in human normal and leukemic stem/progenitor cells

Project description:Hypoxia inducible factors (HIF)1 and 2 are transcription factors which regulate the homeostatic response to low oxygen conditions. Since data related to the importance of HIF1 and 2 in haematopoietic stem and progenitors is conflicting, we investigated the chromatin binding profiles of HIF1 and HIF2 and linked that to transcriptional networks and the cellular metabolic state. Genome-wide ChIP-seq and transcriptome studies revealed that overlapping HIF1- and HIF2-controlled loci were highly enriched for various processes like including metabolism, particularly those involved in glucose metabolism, but also for chromatin organization, cellular response to stress and G protein-coupled receptor signaling. ChIP-qPCR validation studies confirmed that glycolysis-related genes - but not genes related to the TCA cycle or glutaminolysis - were controlled by both HIF1 and HIF2 in leukemic cell lines and primary AMLs, while in healthy human CD34+ cells these loci were predominantly controlled by HIF1 but not HIF2. However, and in contrast to our initial hypotheses, CRISPR/Cas9-mediated knockout of HIF signaling did not affect growth, internal metabolite concentrations, glucose consumption or lactate production under hypoxia. These data indicate that, while HIFs exert control over glycolysis but not OxPHOS gene expression in human leukemic cells, this is not critically important for their metabolic state.

2020-02-04 | GSE123461 | GEO

Genome-wide binding sites of Hypoxia inducible factor 1 (HIF1) and histone modifications

2012-07-12 | GSE39089 | GEO

HIF1 is a master regulator of the adaptive gene expression to hypoxia.

Project description:Total 23 samples were derived from [1] HUVEC treated in the absence (0h) or presence of hypoxia (1, 2, 4, 8, 12, and 24 hrs) to determine hypoxia-regulated gene in endothelial cells, [2] control siRNA or HIF1? siRNA transfected HUVEC cells treated in the absence or presence of hypoxia, [3] control siRNA or KDM3A siRNA transfected HUVEC cells treated in the absence or presence of hypoxia, [4] ChIP-seq data for HIF1 binding sites and histone modifications under normoxia and hypoxia in endothelial cells. This study represents 15 Samples from the gene expression part of the study described in 1,2, and 3 above. The submitter has not provided the ChIP-seq data to GEO.

2012-06-06 | E-GEOD-35932 | biostudies-arrayexpress

Identification of HIF1 and HIF2 target genes in human CB CD34+ cells

2014-03-01 | GSE54662 | GEO

HIF1 is a master regulator of the adaptive gene expression to hypoxia.

Project description:Total 23 samples were derived from [1] HUVEC treated in the absence (0h) or presence of hypoxia (1, 2, 4, 8, 12, and 24 hrs) to determine hypoxia-regulated gene in endothelial cells, [2] control siRNA or HIF1α siRNA transfected HUVEC cells treated in the absence or presence of hypoxia, [3] control siRNA or KDM3A siRNA transfected HUVEC cells treated in the absence or presence of hypoxia, [4] ChIP-seq data for HIF1 binding sites and histone modifications under normoxia and hypoxia in endothelial cells.

2012-06-07 | GSE35932 | GEO

Identification of HIF1 and HIF2 target genes in human CB CD34+ cells

Project description:Although it has been shown that HIF1 and 2 fulfill essential roles within the hematopoietic system and in the regulation of HSC fate, little is currently known about the specific mechanisms that are involved. We identified transcriptome changes induced by hypoxia, constitutively active HIF1(P402/564) and HIF2(P405/531) in human cord blood CD34+ cells. Thus, we were able to identify common hypoxia-HIF1-HIF2 gene signatures, but we also identified specific target genes that were exclusively regulated by HIF1, HIF2 or hypoxia. CB CD34+ cells were isolated by Miltenyi miniMACS column. Cells were prestimulated in HPGM with 100 ng/ml KITL, FLT3L and TPO for 48 hrs. Cells were transduced with control pRRL-IRS2-EGFP lentiviral vectors or vectors expressing HIF1α(P402A,P564A) or HIF2α(P405A,P531A) in one or two rounds of 12 hrs each. 24 hrs later transduced cells were sorted after which RNA was isolated. 5 independent CB CD34+ batches were isolated, transduced and sorted, and isolated RNA was combined and used for Illumina beadhchip arrays HT12 v4

2014-03-01 | E-GEOD-54662 | biostudies-arrayexpress

Genome-wide analysis reveals NRP1 as a critical HIF1-E2F7 target gene in the regulation of motorneuron guidance in vivo

Project description:HIF1 is essential for regulation of the transcriptional response to hypoxia. Recently we showed that the transcriptional repressors E2F7 and E2F8 interact and transcriptionally cooperate with HIF1. Here we further explored this cooperation by performing genome-wide analysis, screening for novel HIF1-E2F7 targets. We show that specifically E2F7 is induced in hypoxia by HIF1. Furthermore, chip-sequencing for E2F7 and HIF1 revealed a large number of common targets of which a subset was also regulated by the complex as examined by microarray analysis. Our data show that the HIF1-E2F7 complex can function both as a repressor or activator. Notably, we identify neuropilin 1 (NRP1) as a novel HIF1-E2F7 target, which is repressed by HIF1-E2F7 in vitro and during zebrafish development, depending on E2F-binding sites present in the NRP1 promoter. In addition we show that regulation of NRP1 by the HIF1-E2F7 complex is required for normal axon guidance of spinal motorneurons in vivo. ChIP-seq analysis of HIF1a and E2F7 binding

2015-12-11 | E-GEOD-66956 | biostudies-arrayexpress

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