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Circadian lncRNA ADIRF-AS1 binds PBAF and regulates renal clear cell tumorigenesis

ABSTRACT: We identified ADIRF-AS1 as a BMAL1-CLOCK regulated circadian lncRNA. Loss of ADIRF-AS1 in U2OS cells altered rhythmicity of clock-controlled genes and expression of genes associated with cell adhesion and the extracellular matrix (ECM) but did not affect neighboring genes in cis. Affinity based enrichment of U2OS ADIRF-AS1-interacting proteins identified all components of the tumor suppressive PBAF (PBRM1/BRG1) complex. Because PBRM1 is a tumor suppressor mutated in 40% of clear cell renal carcinoma (ccRCC) cases, we studied ccRCC 786O cells and also found PBRM1 bound to ADIRF-AS1. Reducing ADIRF-AS1 expression in 786O and A498 ccRCC cells decreased expression of PBAF-suppressed genes, consistent with ADIRF-AS1 acting to antagonize the function of PBAF. Loss of PBRM1, however, rescued PBAF responsive cell cycle genes in ADIRF-AS1 KO 786O ccRCC cells. Importantly, ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant PBRM1 tumors. In this regard, loss of ADIRF-AS1 did not affect in vitro 786O cell growth, but strikingly eliminated in vivo tumorigenesis, which was partially rescued by concurrent loss of PBRM1. This rescue, however, requires Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1 in regulating the ECM. Collectively, our findings suggest that ADIRF-AS1 functions partly to antagonize the tumor suppressive effect of the PBAF complex and behaves as an unforeseen BMAL1-regulated, oncogenic lncRNA.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Chi Dang

PROVIDER: MSV000090286 | MassIVE |

REPOSITORIES: MassIVE

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Circadian lncRNA ADIRF-AS1 binds PBAF and regulates renal clear cell tumorigenesis

Project description:We identified ADIRF-AS1 as a BMAL1-CLOCK regulated circadian lncRNA. Loss of ADIRF-AS1 in U2OS cells altered rhythmicity of clock-controlled genes and expression of genes associated with cell adhesion and the extracellular matrix (ECM) but did not affect neighboring genes in cis. Affinity based enrichment of U2OS ADIRF-AS1-interacting proteins identified all components of the tumor suppressive PBAF (PBRM1/BRG1) complex. Because PBRM1 is a tumor suppressor mutated in 40% of clear cell renal carcinoma (ccRCC) cases, we studied ccRCC 786O cells and also found PBRM1 bound to ADIRF-AS1. Reducing ADIRF-AS1 expression in 786O and A498 ccRCC cells decreased expression of PBAF-suppressed genes, consistent with ADIRF-AS1 acting to antagonize the function of PBAF. Loss of PBRM1, however, rescued PBAF responsive cell cycle genes in ADIRF-AS1 KO 786O ccRCC cells. Importantly, ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant PBRM1 tumors. In this regard, loss of ADIRF-AS1 did not affect in vitro 786O cell growth, but strikingly eliminated in vivo tumorigenesis, which was partially rescued by concurrent loss of PBRM1. This rescue, however, requires Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1 in regulating the ECM. Collectively, our findings suggest that ADIRF-AS1 functions partly to antagonize the tumor suppressive effect of the PBAF complex and behaves as an unforeseen BMAL1-regulated, oncogenic lncRNA.

2022-11-16 | GSE199825 | GEO

Cell State Dependent Effects of Bmal1 on Melanoma Immunity and Tumorigenicity

Project description:The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are often inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM or B16 melanoma cells eliminated clock function, and diminished hypoxic gene expression signature and tumorigenesis, which could be rescued by ectopic expression of HIF-1a. By contrast, over-expressed wild-type or a dominant negative Bmal1 non-canonically sequestered myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM 2.1 cells from a Sox10high to a Sox9high immune resistant, mesenchymal cell state that is found in human melanomas. Our work uncovers a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton.

| MSV000090431 | MassIVE

Regulation of gene expression by miR-101 in U2OS cells

Project description:miR-101 is a tumor suppressive microRNA. Besides EZH2, a well known EZH2 target, miR-101 should have other targets, which might also contribute to its tumor suppressive function. Thus, we performed array hybridization to determine changes in gene expression upon miR-101 overexpression in U2OS cells. U2OS were transfected with synthetic miRNA negative control (NC) or miR-101 for 48hrs, and then harvested for RNA preparation. Three independent experiments were performed. One NC sample were repeated twice for the microarray.

2015-05-22 | E-GEOD-69150 | biostudies-arrayexpress

Regulation of gene expression by miR-101 in U2OS cells

2015-05-22 | GSE69150 | GEO

Non-circadian expression masking clock-driven weak transcription rhythms in U2OS cells

Project description:U2OS cells harbor a circadian clock but express only a few rhythmic genes in constant conditions. We identified 3040 binding sites of the circadian regulators BMAL1, CLOCK and CRY1 in the U2OS genome. Most binding sites even in promoters do not correlate with detectable rhythmic transcript levels. Luciferase fusions reveal that the circadian clock supports robust but low amplitude transcription rhythms of representative promoters. However, rhythmic transcription of these potentially clock-controlled genes is masked by non-circadian transcription that overwrites the weaker contribution of the clock in constant conditions. Our data suggest that U2OS cells harbor an intrinsically rather weak circadian oscillator. The oscillator has the potential to regulate a large number of genes. The contribution of circadian versus non-circadian transcription is dependent on the metabolic state of the cell and may determine the apparent complexity of the circadian transcriptome. Analysis of temporal expression profiles of 5708 expressed genes in synchronized U2OS cells.

2014-05-23 | GSE57891 | GEO

RNA-sequencing in OS-RC-2 cells under the knockdown of Arkadia or ESRP2

Project description:Tumor-specific alternative splicing is implicated in the progression of cancer, including clear cell renal cell carcinoma (ccRCC). Using ccRCC RNA-sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination, and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC. Expression of mRNA in a ccRCC cell line OS-RC-2 under the knockdown of Arkadia or ESRP2. Knock-down of ESRP2 was confirmed by RT-PCR because of low expression of ESRP2 which resulted in non-quantitative FPKM value.

2015-08-01 | E-GEOD-66741 | biostudies-arrayexpress

Interactome of the circadian clock protein PERIOD2 in human U2OS osteosarcoma cells after the resetting of the circadian clock

Project description:Circadian rhythms are a series of endogenous autonomous 24-hour oscillations generated by the circadian clock. At the molecular level, the circadian clock is generated by a transcription-translation feedback loop, where BMAL1 and CLOCK transcription factors of the positive arm activate the expression of CRYPTOCHROME and PERIOD (PER) genes of the negative arm as well as the circadian clock-regulated genes. In this project, we aimed at finding the interactome of PER2 protein in human U2OS osteosarcoma cell line using proximity-dependent biotin identification (BioID) technique. U2OS clones overexpressing PER2-BioID2 or BioID2 were treated with dexamethasone in order to reset the circadian rhythm, and cells were then incubated in biotin-containing media for 12 hours to label the proteins in close proximity of PER2-BioID2. Samples were collected after 36 and 48 hours of the resetting to identify the labeled proteins by mass spectrometry. In addition to known interactors such as CRY1 and CRY2, many novel interactors were identified. In summary, we obtained a network of PER2 interactome and confirmed some of the novel interactions using classical the co-immunoprecipitation method.

2022-04-22 | PXD025179 | Pride

RNA-sequencing in OS-RC-2 cells under the knockdown of Arkadia or ESRP2

2015-08-01 | GSE66741 | GEO

RNA sequencing of livers from Per2-/- and WT mice following MC38 cancer cells injection reveals transcriptional differences as early as 7 days post injection

Project description:The circadian clock regulates diverse physiological processes by maintaining a 24-hour gene expression pattern. Genetic and environmental cues that disrupt normal clock rhythms can lead to cancer, yet the extent to which this effect is controlled by the cancer cells versus non-malignant cells in the tumor microenvironment (TME) is not clear. Here we set out to address this question, by selective manipulation of circadian clock genes in the TME. In two different mouse models of cancer we find that expression of the core clock gene Per2 in the TME is crucial for tumor initiation and metastatic colonization, whereas another core gene, Per1, is dispensable. We further show that loss of Per2 in the TME leads to significant transcriptional changes in response to cancer cell introduction. These changes may contribute to a tumor-suppressive microenvironment. Thus, our work unravels an unexpected protumorigenic role for the core clock gene Per2 in the TME, with potential implications for therapeutic dosing strategies and treatment regimens.

2020-10-15 | GSE156450 | GEO

ChIP-seq of three core components of the circadian clock (BMAL1, CLOCK and CRY1) in unsynchronized human U2OS cells

Project description:The human osteosarcoma cell line U2OS contains a functional circadian clock but expresses only a few rhythmic genes. We identified by ChIP-seq analysis 3040 binding sites of the circadian transcription factors BMAL1, CLOCK, and CRY1 in the genome of U2OS cells, comparable to the number found in highly rhythmic tissues like liver.

2016-02-11 | GSE44236 | GEO

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