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MTR4 drives tumorigenesis of hepatocellular carcinoma by controlling alternative splicing of metabolic genes through PTBP1 recruitment

ABSTRACT: MTR4 drives tumorigenesis of hepatocellular carcinoma by controlling alternative splicing of metabolic genes through PTBP1 recruitment

PROVIDER: PRJNA530680 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8840990_1.fastq.gz	Fastqsanger.gz
	SRR8840990_2.fastq.gz	Fastqsanger.gz
	SRR8840991_1.fastq.gz	Fastqsanger.gz
	SRR8840991_2.fastq.gz	Fastqsanger.gz
	SRR8840986_1.fastq.gz	Fastqsanger.gz

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MTR4 drives tumorigenesis of hepatocellular carcinoma by controlling alternative splicing of metabolic genes through PTBP1 recruitment

Project description:Aberrant alternative splicing (AS) is implicated in cancer metabolic reprogramming that supplies cancer cells with energy and substrates for biosynthesis. Therefore, the elucidation of the mechanism underlying aberrant AS in cancer cells is important for developing specific and effective therapy. We demonstrated that MTR4, a RNA helicase important for RNA quality surveillance, is frequently overexpressed in hepatocellular carcinoma (HCC) and is correlated with increased glycolysis and poor prognosis of HCC patients. MTR4 is required for tumorigenesis of HCC cells by promoting glycolysis and expression of glycolytic genes. MTR4 binds to specific motifs of pre-mRNAs, including those of the key glycolytic genes, and regulates their AS by recruiting PTBP1. We discovered that MTR4 is a direct transcriptional target of c-Myc, suggesting that MTR4 mediates the metabolic function of c-Myc in HCC. These findings reveal mechanisms driving cancer-specific AS profile and present MTR4 as a specific therapeutic target for treating HCC.

2019-12-17 | GSE129263 | GEO

Rip-seq of MTR4 in PLC/PRF5

Project description:Metabolic switch from oxidative phosphorylation to glycolysis is required for tumorigenesis by providing cancer cells with energy and substrates of biosynthesis, and also plays a key role in inducing immune suppressive tumor microenvironment that inhibits tumor immunotherapy. Therefore, to develop more effective cancer therapy, it is important to elucidate mechanisms that control cancer metabolic switch. MTR4 is a RNA helicase associated with nuclear exosome that plays key roles in RNA processing and surveillance. We demonstrated that MTR4 is frequently overexpressed in hepatocellular carcinoma (HCC) and this predicts poor prognosis of HCC patients. MTR4 is required for HCC tumorigenesis by maintaining cancer metabolic switch. Mechanistically, MTR4 is required for the expression of critical glycolytic proteins such as GLUT1 and PKM2 by binding to their pre-mRNA and ensuring correct alternative splicing. c-Myc binds to the promoter of MTR4 gene and is required for MTR4 expression, indicating that MTR4 is a key mediator of c-Myc function in promoting cancer metabolism. These findings reveal an important pathway to drive cancer metabolic switch and present MTR4 as a promising therapeutic target for treating HCC.

2019-12-19 | GSE129261 | GEO

MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus

Project description:Recent in vitro reconstitution analyses have proven that the physical interaction between the exosome core and MTR4 helicase, which promotes the exosome activity, is maintained by either MPP6 or RRP6. However, knowledge regarding the function of MPP6 with respect to in vivo exosome activity remains scarce. Here we demonstrate a facilitative function of MPP6 that composes a specific part of MTR4-dependent substrate decay by the human exosome. Using RNA polymerase II-transcribed poly(A)+ substrate accumulation as an indicator of a perturbed exosome, we found functional redundancy between RRP6 and MPP6 in the decay of these poly(A)+ transcripts. MTR4 binding to the exosome core via MPP6 was essential for MPP6 to exert its redundancy with RRP6. However, at least for the decay of our identified exosome substrates, MTR4 recruitment by MPP6 was not functionally equivalent to recruitment by RRP6. Genome-wide classification of substrates based on their sensitivity to each exosome component revealed that MPP6 deals with a specific range of substrates, and highlights the importance of MTR4 for their decay. Considering recent findings of competitive binding to the exosome between auxiliary complexes, our results suggest that the MPP6-incorporated MTR4-exosome complex is one of multiple alternative complexes rather than the prevailing one.

2022-06-19 | GSE184274 | GEO

tiling hen2 and mtr4-HEN2 is a cofactor of the nuclear exosome in Arabidopsis

Project description:til-ath-2011_3 - tiling hen2 and mtr4 - Identification and comparison of the RNA substrates that accumulate in hen2 and mtr4 mutants. Total RNA extracted from WT, hen2 and mtr4 mutants was used for oligo-dT primed cDNA preparation. Samples were hybridised to NimbleGen whole genome tiling arrays. 8 dye-swapped samples. Gene knockout, genotype comparison, normal vs. transgenic comparison.

2013-06-30 | E-GEOD-48178 | biostudies-arrayexpress

iiCLIP protocol benchmarking with PTBP1

Project description:We describe an improved individual nucleotide resolution CLIP protocol (iiCLIP), which can be completed within 4 days from UV crosslinking to libraries for sequencing. For benchmarking, we directly compared PTBP1 iiCLIP libraries with the iCLIP2 protocol produced under standardised conditions with 1 million HEK293 cells, and with public eCLIP and iCLIP PTBP1 data. There are 3 PTBP1 iiCLIP libraries, 1 input iiCLIP library and 1 PTBP1 iCLIP2 library produced in this study.

2022-08-01 | E-MTAB-10881 | biostudies-arrayexpress

Hydrogen-deuterium exchange mass spectrometry of wt Mtr4 with various RNA substrates

Project description:Mtr4 is a eukaryotic RNA helicase required for RNA decay by the nuclear exosome. Previous studies have shown how RNA enroute to the exosome threads through the highly conserved helicase core of Mtr4. Mtr4 also contains an arch domain, although details of potential interactions between the arch and RNA have been elusive. To understand the interaction of Saccharomyces cerevisiae Mtr4 with various RNAs, we have characterized RNA binding in solution using hydrogen-deuterium exchange mass spectrometry, and affinity and unwinding assays. We have identified RNA interactions within the helicase core that are consistent with existing structures and do not vary between tRNA, single-stranded RNA, and double-stranded RNA constructs. We have also identified novel RNA interactions with a region of the arch known as the fist or KOW. These interactions are important for RNA unwinding and vary in strength depending on RNA structure and length. They account for Mtr4 discrimination between different RNAs. These interactions further drive Mtr4 to adopt a closed conformation characterized by reduced dynamics of the arch arm and intra-domain contacts between the fist and helicase core.

2022-03-07 | PXD031962 | Pride

Xrn1-sensitive lncRNAs accumulate upon inactivation of Dbp2 and Mtr4

Project description:To investigate the role of the helicases Dbp2 and Mtr4 in the decay of Xrn1-sensitive lncRNAs, we performed RNA-Seq in yeast cells lacking Dbp2 or depleted for Mtr4.

2023-07-27 | GSE235552 | GEO

Proteome changes in PTBP1 deficient hematopoietic cells

Project description:Ribosomopathies constitute a range of disabling conditions associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here we demonstrate that deletion of Polypyrimidine Tract Binding Protein 1 (PTBP1) in the hematopoietic compartment led to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 was associated with a decrease in HSC self-renewal, erythroid differentiation and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency led to splicing defects in hundreds of genes and we demonstrate that the up-regulation of a specific isoform of CDC42 could partly mimic the protein synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency was associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA binding proteins.

2022-05-04 | PXD023879 | Pride

tiling hen2 and mtr4-HEN2 is a cofactor of the nuclear exosome in Arabidopsis

2013-06-30 | GSE48178 | GEO

PTBP1 - Modified iCLIP

Project description:PTBP1 - Modified iCLIP

| PRJEB15236 | ENA