CELF1 contributes to aberrant alternative splicing patterns in the type 1 diabetic heart

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

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The evolution of alternative splicing in glioblastoma under therapy

Genome Biology ◽

10.1186/s13059-021-02259-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lin Wang ◽

Karin Shamardani ◽

Husam Babikir ◽

Francisca Catalan ◽

Takahide Nejo ◽

...

Keyword(s):

Alternative Splicing ◽

Standard Of Care ◽

Surface Proteins ◽

Adult Brain ◽

Primary Tumors ◽

Cell Therapies ◽

Therapeutic Development ◽

Human Gbm ◽

Tissue Specimens ◽

Splicing Patterns

Abstract Background Alternative splicing is a rich source of tumor-specific neoantigen targets for immunotherapy. This holds promise for glioblastomas (GBMs), the most common primary tumors of the adult brain, which are resistant to standard-of-care therapy. Although most clinical trials enroll patients at recurrence, most preclinical studies have been done with specimens from primary disease. There are limited expression data from GBMs at recurrence and surprisingly little is known about the evolution of splicing patterns under therapy. Result We profile 37 primary-recurrent paired human GBM specimens via RNA sequencing. We describe the landscape of alternative splicing in GBM at recurrence and contrast that to primary and non-malignant brain-tissue specimens. By screening single-cell atlases, we identify cell-type-specific splicing patterns and novel splicing events in cell-surface proteins that are suitable targets for engineered T cell therapies. We identify recurrent-specific isoforms of mitogen-activated kinase pathway genes that enhance invasiveness and are preferentially expressed by stem-like cells. Conclusion These studies shed light on gene expression in recurrent GBM and identify novel targets for therapeutic development.

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Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration ◽

10.1186/s40035-021-00240-7 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Dunhui Li ◽

Craig Stewart McIntosh ◽

Frank Louis Mastaglia ◽

Steve Donald Wilton ◽

May Thandar Aung-Htut

Keyword(s):

Alternative Splicing ◽

Neurodegenerative Diseases ◽

Messenger Rna ◽

Muscular Atrophy ◽

Single Gene ◽

Synaptic Function ◽

Coding Regions ◽

Splicing Defects ◽

The Impact ◽

Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

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Expression of Alternatively Spliced Sodium Channel α-Subunit Genes

Journal of Biological Chemistry ◽

10.1074/jbc.m406387200 ◽

2004 ◽

Vol 279 (44) ◽

pp. 46234-46241 ◽

Cited By ~ 88

Author(s):

Christopher K. Raymond ◽

John Castle ◽

Philip Garrett-Engele ◽

Christopher D. Armour ◽

Zhengyan Kan ◽

...

Keyword(s):

Alternative Splicing ◽

Sodium Channel ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Genomic Sequence ◽

Molecular Medicine ◽

Primate Model ◽

Α Subunit ◽

Alternatively Spliced ◽

Splicing Patterns

Molecular medicine requires the precise definition of drug targets, and tools are now in place to provide genome-wide information on the expression and alternative splicing patterns of any known gene. DNA microarrays were used to monitor transcript levels of the nine well-characterized α-subunit sodium channel genes across a broad range of tissues from cynomolgus monkey, a non-human primate model. Alternative splicing of human transcripts for a subset of the genes that are expressed in dorsal root ganglia, SCN8A (Nav1.6), SCN9A (Nav1.7), and SCN11A (Nav1.9) was characterized in detail. Genomic sequence analysis among gene family paralogs and between cross-species orthologs suggested specific alternative splicing events within transcripts of these genes, all of which were experimentally confirmed in human tissues. Quantitative PCR revealed that certain alternative splice events are uniquely expressed in dorsal root ganglia. In addition to characterization of human transcripts, alternatively spliced sodium channel transcripts were monitored in a rat model for neuropathic pain. Consistent down-regulation of all transcripts was observed, as well as significant changes in the splicing patterns of SCN8A and SCN9A.

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Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice

Human Molecular Genetics ◽

10.1093/hmg/ddx264 ◽

2017 ◽

Vol 26 (19) ◽

pp. 3797-3807 ◽

Cited By ~ 4

Author(s):

Hieu T. Nguyen ◽

Melissa N. Hinman ◽

Xuan Guo ◽

Alok Sharma ◽

Hiroyuki Arakawa ◽

...

Keyword(s):

Alternative Splicing ◽

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Erk Signaling ◽

Learning Behaviors

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Integrative Visual Analysis of the Effects of Alternative Splicing on Protein Domain Interaction Networks

Journal of Integrative Bioinformatics ◽

10.1515/jib-2008-101 ◽

2008 ◽

Vol 5 (2) ◽

Cited By ~ 1

Author(s):

Dorothea Emig ◽

Melissa S. Cline ◽

Karsten Klein ◽

Anne Kunert ◽

Petra Mutzel ◽

...

Keyword(s):

Alternative Splicing ◽

Protein Interactions ◽

Visual Analysis ◽

Protein Isoforms ◽

Interaction Networks ◽

Protein Domain ◽

Domain Interaction ◽

Exon Arrays ◽

Exon Expression ◽

Splicing Patterns

SummaryProteins and their interactions are essential for the functioning of all organisms and for understanding biological processes. Alternative splicing is an important molecular mechanism for increasing the protein diversity in eukaryotic cells. Splicing events that alter the protein structure and the domain composition can be responsible for the regulation of protein interactions and the functional diversity of different tissues. Discovering the occurrence of splicing events and studying protein isoforms have become feasible using Affymetrix Exon Arrays. Therefore, we have developed the versatile Cytoscape plugin DomainGraph that allows for the visual analysis of protein domain interaction networks and their integration with exon expression data. Protein domains affected by alternative splicing are highlighted and splicing patterns can be compared.

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T.P.1.03 In vitro splicing analysis reveals that availability of a cryptic splice site is not a determinant for alternative splicing patterns caused by +1G>A mutations in introns of the dystrophin gene

Neuromuscular Disorders ◽

10.1016/j.nmd.2009.06.108 ◽

2009 ◽

Vol 19 (8-9) ◽

pp. 577

Author(s):

M. Matsuo ◽

Y. Habara ◽

Y. Takeshima ◽

H. Awano ◽

Y. Okizuka ◽

...

Keyword(s):

Alternative Splicing ◽

Splice Site ◽

Dystrophin Gene ◽

Cryptic Splice Site ◽

In Vitro Splicing ◽

Splicing Patterns

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Snord67 promotes lymph node metastasis and regulates U6-mediated alternative splicing in breast cancer

10.1101/2020.08.28.272617 ◽

2020 ◽

Author(s):

Yvonne L. Chao ◽

Yinzhou Zhu ◽

Hannah J. Wiedner ◽

Yi-Hsuan Tsai ◽

Lily Wilkinson ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Alternative Splicing ◽

Subsequent Development ◽

Distant Metastases ◽

Housekeeping Genes ◽

Small Nuclear Rna ◽

Alternatively Spliced ◽

Rapid Autopsy ◽

Splicing Patterns

AbstractSmall nucleolar RNAs (snoRNAs) have long been considered “housekeeping genes”, important for ribosomal biogenesis and protein synthesis. However, there is increasing evidence that this largely ignored class of non-coding RNAs (ncRNAs) also have wide-ranging, non-canonical functions in diseases, including cancer. SnoRNAs have been shown to have both oncogenic and tumor suppressor roles, yet whether snoRNAs regulate metastasis is unknown. Here we show that expression of certain snoRNAs are enriched in lymph node (LN) metastases in a micro-surgical, immune-competent mouse model of breast cancer. We identify the snoRNA Snord67 as a key regulator of LN metastasis. Knockout of Snord67 resulted in significantly decreased LN tumor growth and subsequent development of distant metastases. This was associated with loss of targeted 2’-O-methylation on the small nuclear RNA U6, a component of the spliceosome. RNA sequencing revealed distinct alternative splicing patterns in Snord67 knockout cells. Using rapid autopsy breast cancer cases, we found that matched human primary tumor and LN metastases revealed similar alternatively spliced genes, including several that are known to contribute to cancer. These results demonstrate that Snord67 is critical for growth of LN metastases and subsequent spread to distant metastases, and suggest that snoRNA-guided modifications of the spliceosome represent a previously unappreciated, yet targetable pathway in cancer.

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