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Alternative RNA Splicing

The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform

Zhiming Zheng – 1st expert on this subject based on the ideXlab platform

  • Oncogenic Splicing factor SRSF3 regulates ILF3 AlteRNAtive Splicing to promote cancer cell proliferation and transformation
    RNA, 2019
    Co-Authors: Masahiko Ajiro, Lulu Yu, Philip Mccoy, Zhiming Zheng

    Abstract:

    : AlteRNAtive RNA Splicing is an important focus in molecular and clinical oncology. We report here that SRSF3 regulates AlteRNAtive RNA Splicing of interleukin enhancer binding factor 3 (ILF3) and production of this double-strand RNA-binding protein. An increased coexpression of ILF3 isoforms and SRSF3 was found in various types of cancers. ILF3 isoform-1 and isoform-2 promote cell proliferation and transformation. Tumor cells with reduced SRSF3 expression produce aberrant isoform-5 and -7 of ILF3. By binding to RNA sequence motifs, SRSF3 regulates the production of various ILF3 isoforms by exclusion/inclusion of ILF3 exon 18 or by selection of an AlteRNAtive 3′ splice site within exon 18. ILF3 isoform-5 and isoform-7 suppress tumor cell proliferation and the isoform-7 induces cell apoptosis. Our data indicate that ILF3 isoform-1 and isoform-2 are two critical factors for cell proliferation and transformation. The increased SRSF3 expression in cancer cells plays an important role in maintaining the steady status of ILF3 isoform-1 and isoform-2.

  • serine arginine rich Splicing factor 3 and heterogeneous nuclear ribonucleoprotein a1 regulate AlteRNAtive RNA Splicing and gene expression of human papillomavirus 18 through two functionally distinguishable cis elements
    Journal of Virology, 2016
    Co-Authors: Masahiko Ajiro, Shuang Tang, John Doorbar, Zhiming Zheng

    Abstract:

    UNLABELLED: Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic pre-mRNAs that are regulated by AlteRNAtive RNA Splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 AlteRNAtive RNA Splicing remain unknown. In this study, an exonic Splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 Splicing and E1^E4 production through interaction with SRSF3, a host oncogenic Splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 Splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 Splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic Splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 Splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 Splicing and reduced E6 expression. These data provide the first evidence that the AlteRNAtive RNA Splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting Splicing factors. IMPORTANCE: Expression of HPV18 genes is regulated by AlteRNAtive RNA Splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 AlteRNAtive RNA Splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 Splicing in the E6 ORF through interaction with a host Splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 Splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how AlteRNAtive RNA Splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host Splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.

  • Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate AlteRNAtive RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements
    Journal of Virology, 2016
    Co-Authors: Masahiko Ajiro, Shuang Tang, John Doorbar, Zhiming Zheng

    Abstract:

    UNLABELLED: Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic pre-mRNAs that are regulated by AlteRNAtive RNA Splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 AlteRNAtive RNA Splicing remain unknown. In this study, an exonic Splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 Splicing and E1^E4 production through interaction with SRSF3, a host oncogenic Splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 Splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 Splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic Splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 Splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 Splicing and reduced E6 expression. These data provide the first evidence that the AlteRNAtive RNA Splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting Splicing factors. IMPORTANCE: Expression of HPV18 genes is regulated by AlteRNAtive RNA Splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 AlteRNAtive RNA Splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 Splicing in the E6 ORF through interaction with a host Splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 Splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how AlteRNAtive RNA Splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host Splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.

Ronald R Breaker – 2nd expert on this subject based on the ideXlab platform

  • control of AlteRNAtive RNA Splicing and gene expression by eukaryotic riboswitches
    Nature, 2007
    Co-Authors: Ming T. Cheah, Andreas Wachter, N. Sudarsan, Ronald R Breaker

    Abstract:

    Riboswitches are elements present in some mRNAs that form AlteRNAtive folded structures depending on the presence or absence of a small molecule ligand. These AlteRNAtive structures determine whether protein is made from the mRNA. Here, a new way by which riboswitches affect protein expression, by affecting AlteRNAtive Splicing, is described. Bacteria make extensive use of riboswitches1,2 to sense metabolites and control gene expression, and typically do so by modulating premature transcription termination or translation initiation. The most widespread riboswitch class known in bacteria responds to the coenzyme thiamine pyrophosphate (TPP)3,4, which is a derivative of vitamin B1. Representatives of this class have also been identified5,6 in fungi and plants, where they are predicted5,7 to control messenger RNA Splicing or processing. We examined three TPP riboswitches in the filamentous fungus Neurospora crassa, and found that one activates and two repress gene expression by controlling mRNA Splicing. A detailed mechanism involving riboswitch-mediated base-pairing changes and AlteRNAtive Splicing control was elucidated for precursor NMT1 mRNAs, which code for a protein involved in TPP metabolism. These results demonstrate that eukaryotic cells employ metabolite-binding RNAs to regulate RNA Splicing events that are important for the control of key biochemical processes.

  • Control of AlteRNAtive RNA Splicing and gene expression by eukaryotic riboswitches
    Nature, 2007
    Co-Authors: Ming T. Cheah, Andreas Wachter, N. Sudarsan, Ronald R Breaker

    Abstract:

    Bacteria make extensive use of riboswitches to sense metabolites and control gene expression, and typically do so by modulating premature transcription termination or translation initiation. The most widespread riboswitch class known in bacteria responds to the coenzyme thiamine pyrophosphate (TPP), which is a derivative of vitamin B1. Representatives of this class have also been identified in fungi and plants, where they are predicted to control messenger RNA Splicing or processing. We examined three TPP riboswitches in the filamentous fungus Neurospora crassa, and found that one activates and two repress gene expression by controlling mRNA Splicing. A detailed mechanism involving riboswitch-mediated base-pairing changes and AlteRNAtive Splicing control was elucidated for precursor NMT1 mRNAs, which code for a protein involved in TPP metabolism. These results demonstrate that eukaryotic cells employ metabolite-binding RNAs to regulate RNA Splicing events that are important for the control of key biochemical processes.

Xuesen Dong – 3rd expert on this subject based on the ideXlab platform

  • Understanding aberrant RNA Splicing to facilitate cancer diagnosis and therapy
    Oncogene, 2020
    Co-Authors: Xuesen Dong, Ruiqi Chen

    Abstract:

    Almost all genes in normal cells undergo AlteRNAtive RNA Splicing to generate a greater extent of diversification of gene products for normal cellular functions. RNA Splicing is tightly regulated and closely interplays with genetic and epigenetic machinery. While DNA polymorphism and somatic mutations modulate AlteRNAtive Splicing patterns, RNA Splicing also controls genomic stability, chromatin organization, and transcriptome. Tumor cells, in turn, often take advantage of aberrant RNA Splicing to develop, grow and progress into therapy-resistant tumors. Understanding AlteRNAtive RNA Splicing in tumor cells would, therefore, provide us opportunities to gain further insights into tumor biology, identify diagnostic or prognosis biomarkers, as well as to design effective therapeutic means to control tumor progression. Here, we provide an overview of RNA Splicing mechanisms and use prostate cancer as an example to review recent advancements in our understanding of RNA Splicing in cancer progression and therapy resistance. We also discuss emerging diagnostic and therapeutic potentials of RNA Splicing events or RNA Splicing factors.

  • AlteRNAtive RNA Splicing of the GIT1 gene is associated with neuroendocrine prostate cancer
    Cancer Science, 2018
    Co-Authors: Varune Rohan Ramnarine, Jessica M. Lovnicki, Xuesen Dong

    Abstract:

    : Potent androgen receptor pathway inhibition (ARPI) therapies have given rise to a lethal, aggressive subtype of castration-resistant prostate cancer (CRPC) called treatment-induced neuroendocrine prostate cancer (t-NEPC). Now, t-NEPC poses a major clinical problem as approximately 20% of CRPC cases bear this subtype-a rate of occurrence that is predicted to rise with the widespread use of ARPI therapies. Unfortunately, there are no targeted therapies currently available to treat t-NEPC as the origin and molecular underpinnings of t-NEPC development remain unclear. In the present study, we identify that RNA Splicing of the G protein-coupled receptor kinase-interacting protein 1 (GIT1) gene is a unique event in t-NEPC patients. Specifically, upregulation of the GIT1-A splice variant and downregulation of the GIT1-C variant expressions are associated with t-NEPC patient tumors, patient-derived xenografts, and cell models. RNA-binding assays show that RNA Splicing of GIT1 is directly driven by SRRM4 and is associated with the neuroendocrine phenotype in CRPC cohorts. We show that GIT1-A and GIT1-C regulate differential transcriptomes in prostate cancer cells, where GIT1-A regulates genes associated with morphogenesis, neural function, environmental sensing via cell-adhesion processes, and epigenetic regulation. Consistent with our transcriptomic analyses, we report opposing functions of GIT1-A and GIT1-C in the stability of focal adhesions, whereby GIT1-A promotes focal adhesion stability. In summary, our study is the first to report that AlteRNAtive RNA Splicing of the GIT1 gene is associated with t-NEPC and reprograms its function involving FA-mediated signaling and cell processes, which may contribute to t-NEPC development.

  • Roles of AlteRNAtive RNA Splicing of the Bif-1 Gene by SRRM4 During the Development of Treatment-induced Neuroendocrine Prostate Cancer
    EBioMedicine, 2018
    Co-Authors: Yinan Li, Zhi Long, Jessica M. Lovnicki, Yuxin Tang, Xiang Chen, Jiaoti Huang, Xuesen Dong

    Abstract:

    Abstract Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that becomes more prevalent when hormonal therapy, chemotherapy, or radiation therapy is applied to patients with metastatic prostate adenocarcinoma (AdPC). How AdPC cells survive these anti-cancer therapies and progress into t-NEPC remains unclear. By comparing the whole transcriptomes between AdPC and t-NEPC, we identified Bif-1, an apoptosis-associated gene, which undergoes AlteRNAtive RNA Splicing in t-NEPC. We found that while Bif-1a is the predominant variant of the Bif-1 gene in AdPC, two neural-specific variants, Bif-1b and Bif-1c, are highly expressed in t-NEPC patients, patient derived xenografts, and cell models. The neural-specific RNA Splicing factor, SRRM4, promotes Bif-1b and Bif-1c Splicing, and the expression of SRRM4 in tumors is strongly associated with Bif-1b/-1c levels. Furthermore, we showed that Bif-1a is pro-apoptotic, while Bif-1b and Bif-1c are anti-apoptotic in PCa cells under camptothecin and UV light irritation treatments. Taken together, our data indicate that SRRM4 regulates AlteRNAtive RNA Splicing of the Bif-1 gene that enables PCa cells resistant to apoptotic stimuli under anti-cancer therapies, and may contribute to AdPC progression into t-NEPC.