Metabolic reprogramming of cancer cells by JMJD6-mediated alternative splicing
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA771064 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16318582_1.fastq.gz | Fastqsanger.gz | |||
| SRR16318582_2.fastq.gz | Fastqsanger.gz | |||
| SRR16318583_1.fastq.gz | Fastqsanger.gz | |||
| SRR16318583_2.fastq.gz | Fastqsanger.gz | |||
| SRR16318584_1.fastq.gz | Fastqsanger.gz |
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Project description:Chromosome 17q gain occurs frequently in MYC-driven tumors including high-risk neuroblastoma. However, the biological consequences of this genetic event remain elusive. Here we show that JMJD6, frequently amplified at the chromosome 17q25 locus, is one of the essential genes to neuroblastoma cells that are engaged in pathways of mitochondrial metabolism, RNA processing and protein homeostasis. JMJD6 cooperates with MYC in cellular transformation and promotes cancer cell proliferation and tumor growth. Mechanistically, JMJD6 physically interacts with RNA-processing machinery to regulate the alternative splicing and protein synthesis. Notably, JMJD6 controls the alternative splicing of glutaminase (GLS), kidney-type glutaminase (KGA) and glutaminase C (GAC), a rate-limiting enzyme of glutaminolysis, and, consequently, the central carbon metabolism in neuroblastoma. Our findings indicate that JMJD6 coordinates with MYC in tumorigenesis by regulating cancer-promoting metabolic programs through an alternative pre-mRNA splicing mechanism.
2023-10-31 | GSE185867 | GEO
Project description:Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, or JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a “molecular glue” that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is coupled with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.
2024-03-11 | GSE248283 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE30995: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [RNA-Seq] GSE31006: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [ChIP-Seq] GSE31007: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [protein binding microarray] GSE31948: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [AS microarray] Refer to individual Series
2011-09-14 | E-GEOD-30992 | biostudies-arrayexpress
Project description:Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor
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Project description:Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we perform a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identify components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we show in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming. Examination of Myc-chromatin interactions in reprogramming cells
2015-04-15 | E-GEOD-67694 | biostudies-arrayexpress
Project description:Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we perform a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identify components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we show in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming. Examination of 2 Gcn5-chromatin interactions in mouse embryonic stem cells
2015-04-15 | E-GEOD-67710 | biostudies-arrayexpress
Project description:Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we perform a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identify components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we show in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming. Examination of expression level changes at D0 and D2 MEFs
2015-04-15 | E-GEOD-67715 | biostudies-arrayexpress
Project description:The 2-oxoglutarate dependent protein JMJD6 acts as a lysyl hydroxylase on specific residues of the splicing factor U2AF2. To understand the molecular roles of JMJD6 in normal haematopoiesis and identify any role of JMJD6 in splicing, we performed RNA-sequencing on Lin-Sca1+Kit+ (LSK) haematopoietic stem and progenitor cells (HSPCs) derived from young mice.
2021-03-05 | GSE168283 | GEO
Project description:Post-transcriptional modifications of tumor suppressors, including microRNA-mediated downregulation, are important events in tumor progression. To identify microRNAs involved in oncogenic transformation, we examined global microRNA profiles of three ras transgenic zebrafish models. Four microRNAs are upregulated in all transgenic systems. Analysis of the predicted targets shows that three of them target Jmjd6, and overexpression of Jmjd6 in ras transformed melanocytes blocks proliferation and melanoma development. We found that Jmjd6 functions to regulate splicing of the tumor suppressor cdkn1a/p21. Truncated cdkn1a/p21 transcripts, lacking the PCNA binding domain, accumulate in ras-expressing melanocytes during melanoma development. These findings implicate Jmjd6 in a novel mechanism for inactivation of a major tumor suppressor pathway in melanoma.
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Project description:Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we perform a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identify components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we show in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming.
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