RNA-seq analysis in fibroblast IMR90 CTRL/MYC/MYC+SF3B1 KD
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ABSTRACT:
PROVIDER: PRJNA783790 | ENA |
REPOSITORIES: ENA
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Project description:RNA-seq analysis in fibroblast IMR90 CTRL/MYC/MYC+SF3A3 KD
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Project description:SF3B1 is the most mutated splicing factor (SF) in myelodysplastic syndromes (MDS), clonal hematopoietic disorders with variable risk of leukemic transformation. Although the tumorigenic effects of SF3B1 mutations have been defined, the role of “non-mutated” SF3B1 in cancer remains largely unresolved. Here we identify a conserved epitranscriptomic program that steers SF3B1 translation to counteract leukemogenesis. Our analysis of human and murine pre-leukemic MDS cells reveals a remarkable SF3B1 protein increase. Selective inhibition of SF3B1 upregulation accelerates MDS-to-leukemia progression in vivo. Mechanistically, ALKBH5-driven m6A demethylation within the SF3B1 5’ UTR fine-tunes SF3B1 translation to direct splicing of central DNA repair and epigenetic regulators during transformation. Loss of 5’ UTR m6A increases SF3B1 abundance, genome stability and delays leukemia progression in vivo, supporting integrative analysis of SF3B1 molecular signatures in humans that may predict tumor mutational burden and poor prognosis. These findings highlight a post-transcriptional gene expression nexus that unveils unanticipated SF3B1-dependent cancer vulnerabilities.
2023-03-21 | GSE189585 | GEO
Project description:Splicing is a central RNA-based process commonly altered in human cancers; however, how the splicing machinery is co-opted during tumorigenesis remains largely unresolved. Here we identify the splice factor SF3A3 at the nexus of an oncogenic translation program that rewires splicing to promote tumorigenesis. Our results suggest that key spliceosomal networks centered on the essential core U2-associated factor, SF3A3, are exquisitely controlled at the translation level during oncogenic stress. Upon oncogene activation, SF3A3 translation is rapidly enabled via a conserved internal stem-loop structure embedded in the transcript 5’ untranslated region (UTR). Uncoupled SF3A3 translation leads to alternative splicing of several mRNAs involved in mitochondrial dynamics, and induces a metabolic switch that fuels cancer initiation properties in MYC-driven breast tumorigenesis in vivo. Finally, we compelling show that SF3A3 is post-transcriptionally altered and predicts for poor prognosis in aggressive triple negative breast cancers. Together, these findings unveil a highly dynamic regulatory network that interfaces mRNA splicing and translation to orchestrate cancer gene expression networks.
2021-03-25 | GSE147505 | GEO
Project description:Although mutations in the RNA splicing factor SF3B1 are frequently observed in multiple human cancers, their functional role in promoting tumorigenesis and therapeutic significance remain poorly understood. Here we characterize the splicing landscape of 79 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3’ splice site (ss) events shared as well as specific to different tumor types. Regulatory network analysis shows that tumors harboring the most common hotspot mutation in SF3B1 (SF3B1K700E) activate the MYC transcriptional program. SF3B1 mutations lead to a dramatic decay of transcripts encoding the key PP2A phosphatase subunit PPP2R5A due to aberrant 3’ss usage, resulting in increased c-MYC serine 62 phosphorylation (allowing MYC to escape ubiquitin-mediated degradation) and in increased BCL2 serine 70 phosphorylation (leading to anti-apoptotic effects). This effect of SF3B1K700E on c-MYC and BCL2 activation through post-translational regulation was conserved across human and mouse cells and could be rescued by restored expression of PPP2R5A. Consonant with this, mutant SF3B1 promoted c-MYC driven tumorigenesis could be restored by the PP2A activating agent FTY-720. This study reveals the functional contribution of mutant SF3B1 to tumorigenesis through regulation of established oncogenic pathways and provides therapeutic strategies for related tumors.
2020-05-01 | GSE116391 | GEO
Project description:RNA-sequencing data from HEK293T and HAP1 cell models: Hek293T (SF3B1-K700E, SF3B1-WT, SUGP1-KD and siContol), HAP1 CRISPR-isogenic cell lines WT and SUGP1-P636L
2020-10-10 | GSE159304 | GEO
Project description:Knockdown of mutant and/or wild-type SF3B1 in MEL202 cell line by Degron knock-in, followed by RNA-seq, to identify splicing events governed by mutant SF3B1. Control: parental MEL202 cell line. Experiments: mutant-SF3B1 knockdown; wildtype-SF3B1 knockdown; mutant SF3B1 knockout. Treatments: each of these four conditions plus and minus shld.
2015-03-11 | E-GEOD-66719 | biostudies-arrayexpress
Project description:To understand how KD regulates gene expression, the gene expression profiles of livers from mice fed a control (Ctrl) or KD are compared using RNA-seq
2023-07-29 | GSE238099 | GEO
Project description:Gene expression data from IMR90 Control, IMR90 HRAS-G12V, IMR90 HRAS-G12V+shDOT1L, IMR90 DOT1L Overexpression
| PRJNA658579 | ENA
Project description:Mutations in splicing factor SF3B1 promote transformation through MYC stabilization
| PRJNA478381 | ENA