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Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [RNA-Seq]

ABSTRACT: Transcription regulators and apparatuses compartmentalize into transcriptional condensates in part through molecular interactions among intrinsically disordered regions. To better understand how these fundamental condensates are regulated, we performed time-series analyses of transcriptome, genome and imaging to show that the previously characterized molecular chaperone RUVBL2 assembles Pol II condensates by its ATPase activity and prevalently interacting with diverse oncogenic transcription factors at promoters, thereby maintaining active transcription in mammalian cells. Besides, RUVBL2 is overexpressed in various cancers, has higher expression levels and preferential chromatin binding compared with RUVBL1. Remarkably, acute protein degradation and chemical perturbations of RUVBL2 with the nucleoside compound cordycepin result in the repression of oncogenes in embryonic stem cells and breast cancer cells, respectively. Our results suggest that molecular chaperone RUVBL2 safeguards the hemostasis of transcriptional condensates at promoters. Thus, pharmacological perturbations of RUVBL2 is a promising strategy to restore these condensates in breast cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE160698 | GEO | 2022/08/30

REPOSITORIES: GEO

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Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [PRO-Seq]

Project description:Transcription regulators and apparatuses compartmentalize into transcriptional condensates in part through molecular interactions among intrinsically disordered regions. To better understand how these fundamental condensates are regulated, we performed time-series analyses of transcriptome, genome and imaging to show that the previously characterized molecular chaperone RUVBL2 assembles Pol II condensates by its ATPase activity and prevalently interacting with diverse oncogenic transcription factors at promoters, thereby maintaining active transcription in mammalian cells. Besides, RUVBL2 is overexpressed in various cancers, has higher expression levels and preferential chromatin binding compared with RUVBL1. Remarkably, acute protein degradation and chemical perturbations of RUVBL2 with the nucleoside compound cordycepin result in the repression of oncogenes in embryonic stem cells and breast cancer cells, respectively. Our results suggest that molecular chaperone RUVBL2 safeguards the hemostasis of transcriptional condensates at promoters. Thus, pharmacological perturbations of RUVBL2 is a promising strategy to restore these condensates in breast cancers.

2022-08-30 | GSE160696 | GEO

Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [Mnase-seq]

2022-08-30 | GSE185347 | GEO

Molecular Chaperone RUVBL2 Activates Oncogenes by Modulation of Transcriptional Condensates [ChIP-Seq]

2022-08-30 | GSE160738 | GEO

ChIP-seq from Human U2OS Cell for CRY2 and RUVBL2 with DMSO or Cordycepin Treatment

Project description:To evaluate the effects of cordycepin on CRY2 and RUVBL2 binding on the chromatin sites, non-synchronized U2OS cells were treated with cordycepin (100 uM) for 1 h, then performed ChIP-seq. We found that cordycepin relieves CRY2 and RUVBL2 proteins from the chromatin for more than 60-70%.

2020-05-07 | GSE130507 | GEO

RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer

Project description:RUVBL1 and RUVBL2 (collectively RUVBL1/2) are essential AAA+ ATPases that function as co-chaperones and have been implicated in cancer. Here we investigated the molecular and phenotypic role of RUVBL1/2 ATPase activity in non-small cell lung cancer (NSCLC). We find that RUVBL1/2 are overexpressed in NSCLC patient tumors, with high expression prognostic of poor survival. Utilizing a highly specific inhibitor of RUVBL1/2 ATPase activity, we show that RUVBL1/2 ATPase activity is necessary for the maturation of the PAQosome, a large RUVBL1/2-dependent multiprotein complex. We also show that RUVBL1/2 have roles in DNA replication, as inhibition of their ATPase activity impedes RPA loading at replication forks, decreases fork stability, and ultimately results in replication catastrophe and cancer cell death. While in vivo pharmacological inhibition of RUVBL1/2 results in modest antitumor activity, it synergizes with radiation in NSCLC, but not normal cells, an attractive property for future preclinical development.

2019-12-18 | GSE107637 | GEO

Mouse Liver Chromatin Circadian ChIP_seq for Bmal1 and Ruvbl2

Project description:Mouse livers were collected at 4 hours interval at constant darkness condition after 2 weeks synchronization to ambient light dark cycle, then conducted for the ChIP-seq (Bmal1, Ruvbl2). We found Ruvbl2 rhythmically co-occupancies with Bmal1 binding sites.

2020-05-07 | GSE130505 | GEO

Expression analysis of THP1 cells following shRNA knock-down of RUVBL2

Project description:We used an inducible shRNA system and RNA-Seq to examine gene expression changes in acute myeloid leukemia THP1 cells following silencing of RUVBL2. RUVBL2 is a AAA+ ATPase that functions in a number of cellular processes, including chromatin remodeling and trnascriptional control, and is critical for survival of acute myeloid leukemia cells and in vivo disease progression.

2018-10-31 | GSE105253 | GEO

RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer

Project description:RUVBL1/RUVBL2 ATPase Activity Drives PAQosome Maturation, DNA Replication and Radioresistance in Lung Cancer

| PRJNA420950 | ENA

ChIP-seq from Human U2OS Cell for BMAL1, CRY1, CRY2 and RUVBL2

Project description:To evaluate the chromatin binding of BMAL1, CRY1, CRY2 and RUVBL2 in U2OS cells.

2020-05-07 | GSE130602 | GEO

LOXL2-mediated chromatin compaction is required to maintain the oncogenic properties of triple-negative breast cancer cells

Project description:Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase–like 2 (LOXL2). This histone modification is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here we show that LOXL2 interacts with RUVBL1, RUVBL2, BAF53, and DMAP1, a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2-dependent chromatin compaction. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC-seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA-MB-231).

2023-12-31 | GSE142463 | GEO

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