AMPKα2 binds to chromatin to regulate gene expression in ALL cells [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210213 | GEO | 2023/12/06
REPOSITORIES: GEO
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Project description:To identify genome-wide genes regulated by direct association of AMPK to chromatin in response to energy/metabolic stress, we constructed CCRF-CEM (T-ALL) stable cell lines expressing HA-AMPKα2 and performed ChIP-seq and RNA-seq assays in control or glucose deprivation conditions. ChIP-seq and RNA-seq analysis identified the histone genes as a subset of genes regulated by AMPK with direct AMPKα2 occupancy at their TSS region.
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Project description: ABSTRACT POLR2A encodes RPB1, the largest subunit of the RNA polymerase II (pol II) complex, which is responsible for transcription of all ~21,000 protein-encoding genes. Here we describe the first fifteen patients harboring de novo heterozygous variants in POLR2A. The majority presents with profound infantile onset hypotonia and developmental delay. Missense variants that were expected to exert only mild structural effects, lead to malfunctioning RPB1, thereby inducing a dominant negative effect on pol II function. Intriguingly, these patients presented with a severe clinical phenotype. Conversely, variants expected to result in loss-of-function, leading to reduced availability of RPB1 were better tolerated: these patients exhibited the mildest phenotypes.
2019-09-02 | PXD011355 | Pride
Project description:RPB1-specific ubiquitin ligase (E3) controls the degradation of this largest subunit of Pol II and consequently the Pol II pool size. Although several RPB1-specific E3s have been documented, their function is only revealed in cells with massive DNA damage. We demonstrated that ARMC5 physically interacted with cullin3 (CUL3) and RPB1. ARMC5 is an armadillo domain-containing protein with unknown mechanisms of action. ARMC5 deletion caused significant RPB1 accumulation in all the major organs under a physiological condition in the absence of artificially induced DNA damage. This is accompanied by reduced RPB1 ubiquitination. In vitro ubiquitination assay proved that ARMC5, CUL3, and RBX1 formed an effective E3 for RPB1. RPB1 was confirmed as being highly accumulated in the adrenal gland nodules from PBMAH patients with mutations in the ARMC5 coding sequence. Surprisingly, the compromised RPB1 degradation did not lead to increased Pol II stalling according to ChIP-Seq, or a general decrease of gene transcription according to RNA-seq. On the contrary, among 1486 differentially expressed genes in the KO adrenal glands, 93.5% of them were upregulated, probably due to the enlarged Pol II pool size. Our results showed that the ARMC3-CUL3 E3 was the dominant E3 in normal cells and organs and controlled Pol II pool size. The abnormally large Pol II pool size due to ARMC5 mutation dysregulated a large number of genes that in turn led to many phenotypes, including PBMAH in humans.
2022-05-20 | GSE169578 | GEO
Project description:RPB1-specific ubiquitin ligase (E3) controls the degradation of this largest subunit of Pol II and consequently the Pol II pool size. Although several RPB1-specific E3s have been documented, their function is only revealed in cells with massive DNA damage. We demonstrated that ARMC5 physically interacted with cullin3 (CUL3) and RPB1. ARMC5 is an armadillo domain-containing protein with unknown mechanisms of action. ARMC5 deletion caused significant RPB1 accumulation in all the major organs under a physiological condition in the absence of artificially induced DNA damage. This is accompanied by reduced RPB1 ubiquitination. In vitro ubiquitination assay proved that ARMC5, CUL3, and RBX1 formed an effective E3 for RPB1. RPB1 was confirmed as being highly accumulated in the adrenal gland nodules from PBMAH patients with mutations in the ARMC5 coding sequence. Surprisingly, the compromised RPB1 degradation did not lead to increased Pol II stalling according to ChIP-Seq, or a general decrease of gene transcription according to RNA-seq. On the contrary, among 1486 differentially expressed genes in the KO adrenal glands, 93.5% of them were upregulated, probably due to the enlarged Pol II pool size. Our results showed that the ARMC3-CUL3 E3 was the dominant E3 in normal cells and organs and controlled Pol II pool size. The abnormally large Pol II pool size due to ARMC5 mutation dysregulated a large number of genes that in turn led to many phenotypes, including PBMAH in humans.
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Project description:To identify genes transcriptionally regulated under energy/metabolic stress, we treated CCRF-CEM/HA-AMPKa2 cells with Glucose deprivation condition for 24 hours, and examined their RNA profile using RNA-Seq. More than 3000 genes was altered (Fold Change > 1.5 or < -1.5, q value < 0.05) under energy/metabolic stress (glucose deprivation) vs. control, with approximately 60-70% genes exhibiting downregulation, whereas the remainder show upregulation. Note: sample headers in data_matrix_ctrl_no_glucose.txt, CTRL_7: Ctrl rep1 sample count number; CTRL_8: Ctrl rep2 count number; ONG_9: No glucose rep1 count number; ONG_10: No glucose rep2 count number;
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Project description:Bortezomib is a proteasome inhibitor used in severel different hematological malignancies. Resistance to this drug is still poorly understood. In order get more insight in the resistance mechanism, we developed several bortezomib resistant subclones of the CCRF-CEM T-ALL cell line. On these subclones comparative Genome hybridization (arrayCGH) for DNA copy number analysis gene expression and micro-RNA expression arrays were performed. We performed micro-RNA on two different bortezomib resistant subclones of the CCRF-CEM cell line. The resistant subclones were compared to the parental CCRF-CEM wildtype cell line.
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Project description:UBE2O is localized in the 17q25 locus, which is known to be amplified in human cancers, but its role in tumorigenesis remains undefined. Here we show that Ube2o deletion in MMTV-PyVT or TRAMP mice profoundly impairs tumor initiation, growth and metastasis, while switching off the metabolic reprogramming of tumor cells. Mechanistically, UBE2O specifically targets AMPKα2 for ubiquitination and degradation, and thereby promotes activation of the mTOR-HIF1α pathway. Notably, inactivation of AMPKα2, but not AMPKα1, abrogates the tumor attenuation caused by UBE2O-loss, while treatment with rapamycin or inhibition of HIF1α ablates UBE2O-dependent tumor biology. Finally, pharmacological blockade of UBE2O inhibits tumorigenesis through the restoration of AMPKα2, suggesting the UBE2O-AMPKα2 axis as a potential cancer therapeutic target.
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Project description:Bortezomib is a proteasome inhibitor used in severel different hematological malignancies. Resistance to this drug is still poorly understood. In order get more insight in the resistance mechanism, we developed several bortezomib resistant subclones of the CCRF-CEM T-ALL cell line. On these subclones comparative Genome hybridization (arrayCGH) for DNA copy number analysis gene expression and micro-RNA expression arrays were performed. We performed comparative Genome hybridization (arrayCGH) for DNA copy number analysis on four different bortezomib resistant subclones of the CCRF-CEM cell line. The resistant subclones were compared to the parental CCRF-CEM wildtype cell line and reference DNA.
2015-11-04 | E-GEOD-74633 | biostudies-arrayexpress
Project description:Bortezomib is a proteasome inhibitor used in severel different hematological malignancies. Resistance to this drug is still poorly understood. In order get more insight in the resistance mechanism, we developed several bortezomib resistant subclones of the CCRF-CEM T-ALL cell line. On these subclones comparative Genome hybridization (arrayCGH) for DNA copy number analysis gene expression and micro-RNA expression arrays were performed. We performed gene expression microarray analysis on four different bortezomib resistant subclones of the CCRF-CEM cell line. The resistant subclones were compaired to treated and untreated the parental CCRF-CEM wildtype cell line.
2015-11-04 | E-GEOD-74634 | biostudies-arrayexpress