SAM68-specific splicing is required for proper selection of alternative 3'UTR isoforms in the nervous system
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ABSTRACT:
PROVIDER: PRJNA433317 | ENA |
REPOSITORIES: ENA
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Project description:Neuronal alternative splicing is dynamically regulated in a spatiotemporal fashion. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs governed by STARs remains unclear. We deciphered the alternative splicing programs of SAM68 and SLM1 proteins using transcriptomics. We reveal that SAM68 and SLM1 encode distinct alternative splicing programs; SAM68 preferentially controls alternative last exon (ALE) splicing. Interleukin 1-receptor accessory protein (Il1rap) is a novel target for SAM68. The usage of Il1rap ALEs results in mainly two variants encoding two functionally different isoforms, a membrane-bound (mIL1RAcP) and a soluble (sIL1RAcP) type. The brain exclusively expresses mIL1RAcP. SAM68 knockout results in remarkable conversion into sIL1RAcP in the brain, which significantly disturbs IL1RAcP neuronal function. Thus, we uncover the critical role of proper neuronal isoform selection through ALE choice by the SAM68-specific splicing program.
2019-12-29 | GSE110258 | GEO
Project description:Neuronal alternative splicing is a core mechanism for functional diversification. We previously found that STAR family proteins (SAM68, SLM1, SLM2) regulate spatiotemporal alternative splicing in the nervous system. However, the whole aspect of alternative splicing programs by STARs remains unclear. Here, we performed a transcriptomic analysis using SAM68 knockout and SAM68/SLM1 double-knockout midbrains. We revealed different alternative splicing activity between SAM68 and SLM1; SAM68 preferentially targets alternative 3' UTR exons. SAM68 knockout causes a long-to-short isoform switch of a number of neuronal targets through the alteration in alternative last exon (ALE) selection or alternative polyadenylation. The altered ALE usage of a novel target, interleukin 1 receptor accessory protein (Il1rap), results in remarkable conversion from a membrane-bound type to a secreted type in Sam68KO brains. Proper ALE selection is necessary for IL1RAP neuronal function. Thus the SAM68-specific splicing program provides a mechanism for neuronal selection of alternative 3' UTR isoforms.
| S-EPMC6909182 | biostudies-literature
Project description:The proper subcellular localization of RNAs and local translational regulation is crucial in highly compartmentalized cells, such as neurons. RNA localization is mediated by specific cis-regulatory elements usually found in mRNA 3'UTRs. Therefore, processes that generate alternative 3'UTRs – alternative splicing and polyadenylation – have the potential to diversify mRNA localization patterns in neurons. Here, we performed mapping of alternative 3'UTRs in neurites and soma isolated from mESC-derived neurons. Our analysis identified 593 genes with differentially localized 3'UTR isoforms. In particular, we have shown that two isoforms of Cdc42 gene with distinct functions in neuronal polarity are differentially localized between neurites and soma of mESC-derived and mouse primary cortical neurons, at both mRNA and protein level. Using reporter assays and 3'UTR swapping experiments, we have identified the role of alternative 3’UTRs and mRNA transport in differential localization of alternative CDC42 protein isoforms. Moreover, we used SILAC to identify isoform-specific Cdc42 3'UTR-bound proteome with potential role in Cdc42 localization and translation. Our analysis points to usage of alternative 3'UTR isoforms as a novel mechanism to provide for differential localization of functionally diverse alternative protein isoforms.
2018-12-07 | PXD011518 | Pride
Project description:Male germ cells express the widest repertoire of transcript variants in mammalian tissues. Nevertheless, factors and mechanisms underlying such pronounced diversity are largely unknown. The splicing regulator Sam68 is highly expressed in meiotic cells and its ablation results in defective spermatogenesis. Herein, we uncover an extensive splicing program operated by Sam68 across meiosis, primarily characterized by alternative last exon (ALE) regulation in genes of functional relevance for spermatogenesis. Lack of Sam68 preferentially causes premature transcript termination at internal polyadenylation sites.
2019-03-12 | GSE122929 | GEO
Project description:We uncover a Sam68-dependent splicing program during cerebellar development. These events direct proper isoform expression of the genes required to guarantee the establishment of the correct spatial/temporal neural circuitry. The dysregulation in Sam68 null mice leads to functional defects in adult neurons
2020-06-01 | GSE133711 | GEO
Project description:Sam68 insures proper 3'-end pre-mRNA processing during germ cell differentiation
| PRJNA506952 | ENA
Project description:The number of known long noncoding RNA (lncRNA) functions is rapidly growing, but how those functions are encoded in their sequence and structure remains poorly understood. NORAD is a recently characterized, abundant, and highly conserved cytoplasmic lncRNA that is required for proper mitotic divisions in human cells. NORAD antagonizes repressors from the Pumilio family that bind at least 17 sites spread through 12 repetitive units in NORAD sequence. Here we study conserved sequences in NORAD repeats, identify additional interacting partners, and characterize the interaction between NORAD and the RNA binding protein SAM68 (KHDRBS1), which is required for NORAD function in antagonizing Pumilio. The interactions between NORAD, Pumilio and SAM68 provide a paradigm for how specific repeated and structured elements with a lncRNA can facilitate its function.
2019-01-01 | GSE104856 | GEO
Project description:SAM68 is an RNA binding protein frequently up-regulated in several human cancers and its oncogenic activity has often been associated with its splicing activity. Nevertheless, the genome-wide impact of SAM68 on the transcriptome of cancer cells is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 SAM68-silenced cells, we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this splicing factor.
2022-04-04 | GSE140754 | GEO
Project description:The metabolic conversion of oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling the tumor metabolic switch is still not entirely clear. Here we demonstrate that SAM68 (gene name: KHDRBS1) as a splicing regulatory factor is frequently overexpressed in Lung adenocarcinoma (LUAD) and negatively correlated with the prognosis of LUAD patients. we find SAM68 promotes LUAD cells tumorigenesis and metastasis both in vitro and in vivo by regulating cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of Pyruvate kinase (PKM) pre-mRNAs, finally promoting the formation of PKM2. Mechanically, Sam68 interacted with the splicing repressor hnRNP A1, and depletion of hnRNP A1 or mutations that impair this interaction attenuated the PKM splicing regulation. Together, our work demonstrates key roles of SAM68 in the cancer metabolic conversion by regulating alternative splicing and SAM68 may be a promising therapeutic target for treating LUAD.This project looks into how SAM68 levels affect cancer cell phenotype in vitro
2020-11-04 | GSE149120 | GEO
Project description:The changes in the transcriptome via Sam68-knockdown were investigated in oral squamous cell carcinoma cells. The candidate genes which are regulated by Sam68 were demonstrated.
2022-07-28 | GSE202136 | GEO