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    Regulation of mRNA Splicing by Signal Transduction

    Regulation of mRNA Splicing by Signal Transduction

    By: Gretchen Edwalds-Gilbert, Ph.D. (Joint Science Dept., The Claremont Colleges) © 2010 Nature Education

    Citation: Edwalds-Gilbert, G. (2010) Regulation of mRNA Splicing by Signal Transduction. Nature Education 3(9):43

    How can only 25,000-30,000 protein-coding genes in humans produce the massive variety of proteins, cells, and tissues that exist in our bodies? The answer: alternative splicing.

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    How can only 25,000–30,000 protein-coding genes in humans produce the massive variety of proteins, cells, and tissues that exist in our bodies? Alternative splicing is one major mechanism that makes the most of the precursor messenger RNAs (pre-mRNAs) transcribed from these few genes by processing the pre-mRNA into a diverse array of mature mRNAs that encode distinct proteins. Signal transduction pathways and cell cycle regulation are directly tied with regulation of alternative splicing. Scientists estimate that 15–60 percent of human genetic diseases involve splicing errors, making understanding splicing mechanisms and regulation an important area of research.

    What Is Alternative Splicing, and Why Is It Important?

    When scientists analyzed the initial sequence of the human genome, they were surprised by the relatively small number of protein-coding genes in humans compared with less complex organisms, such as fruit flies. How can so few genes encode all the information found in human cells?

    Figure 1: A schematic representation of alternative splicing

    The figure illustrates different types of alternative splicing: exon inclusion or skipping, alternative splice-site selection, mutually exclusive exons, and intron retention. For an individual pre-mRNA, different alternative exons often show different types of alternative-splicing patterns.

    © 2002 Nature Publishing Group Cartegni, L., Chew, S. L., & Krainer, A. R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. 3, 285–298 (2002). All rights reserved.

    Genomic DNA is like a word-processing document that is "read-only" with no changes possible, whereas the RNA is a transcript of the document that permits, and even requires, cutting and pasting to get to the final version. Changes in cutting and pasting alter the meaning of the document, often quite dramatically. Similarly, alternative splicing of RNA leads to a variety of possible mRNA isoforms and proteins, which can have different, and often opposing, functions (Figure 1). Sequences called exons are regions of the pre-mRNA that are included in the mature mRNA, such as the protein-coding sequences and regulatory untranslated regions at either end of the mRNA. Sequences called introns are the portions of the pre-mRNA that are removed during splicing. In alternative splicing, some sequences serve as exons under some conditions and are included in the final mRNA. At other times, however, the alternative-splicing process may exclude the same sequence, treating it as an intron and removing it from the mature mRNA.

    A critical finding regarding the prevalence of alternative splicing was that a majority of human genes produce a wide variety of messenger RNAs (mRNA) that in turn encode distinct proteins (Johnson 2003). Scientists estimate that 15–60 percent of human genetic diseases involve splicing mutations, either through direct mutation of the splice-site signals or through disruption of other components of the splicing pathway (Wang & Cooper 2007). Therefore, understanding what information in pre-mRNAs determines alternative splicing and how cells regulate alternative splicing is of critical importance.

    How does the splicing machinery distinguish between exons, which are part of the mature mRNA, and introns, which are removed from the pre-mRNA? Alternative splicing adds an extra layer of complexity, because regulatory sequences that sometimes designate an exon's inclusion into the mature mRNA dictate the exclusion of that exon under other conditions.

    RNA splicing requires specific sequences in the pre-mRNA that mark where introns and exons are located. Occasionally, mutations in these sequences can lead to the production of mRNAs that are out of frame or unstable. Such mutations cause a problem with protein production despite the mutation being in noncoding sequence. The process of splicing is concurrent with mRNA transcription, with possible splicing regulatory roles for factors involved in chromatin structure, transcription, and other steps (Nilsen & Graveley 2010).

    How Do Scientists Identify Alternatively Spliced mRNAs?

    Scientists have estimated the prevalence of alternative splicing on a genome-wide scale using high-throughput approaches including microarrays, analysis of expressed sequence tags, and sequencing (Wang 2008). In these experiments, scientists isolate RNA from cells and then convert it into complementary DNA, or cDNA, which they can tag with a fluorescent label during the reverse transcription process. They then analyze the cDNA through its ability to bind to small fragments of DNA tethered to a small chip, or microarray. If the chip includes DNA sequences that span exon-intron junctions or other sequences designating an alternatively spliced mRNA, then scientists can detect how common that alternatively spliced isoform is relative to other forms of the same pre-mRNA. In addition, they can also compare the splice isoforms among different tissues or developmental stages. Direct sequencing of the spliced mRNA is another technique researchers use to determine the frequency of alternatively spliced mRNA. Again, scientists isolate RNA from cells and then reverse transcribe it into the more stable cDNA for further analysis.

    Source : www.nature.com

    Mechanism of alternative splicing and its regulation

    Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process ...

    Biomed Rep. 2015 Mar; 3(2): 152–158.

    Published online 2014 Dec 17. doi: 10.3892/br.2014.407

    PMCID: PMC4360811 PMID: 25798239

    Mechanism of alternative splicing and its regulation

    YAN WANG,1,* JING LIU,1,* BO HUANG,1 YAN-MEI XU,1 JING LI,2 LIN-FENG HUANG,1 JIN LIN,1 JING ZHANG,1 QING-HUA MIN,1 WEI-MING YANG,1 and XIAO-ZHONG WANG1

    Author information Article notes Copyright and License information Disclaimer

    This article has been cited by other articles in PMC.

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    Abstract

    Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing. All these factors contributing to this one fundamental biological process add up to a mechanism that is critical to the proper functioning of cells. Any corruption of the process may lead to disruption of normal cellular function and the eventuality of disease. Cancer is one of those diseases, where alternative splicing may be the basis for the identification of novel diagnostic and prognostic biomarkers, as well as new strategies for therapy. Thus, an in-depth understanding of alternative splicing regulation has the potential not only to elucidate fundamental biological principles, but to provide solutions for various diseases.

    Keywords: alternative splicing, regulation, precursor mRNA, mechanism, disease

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    1. Introduction

    The discovery of the phenomenon that viral sequences are removed from a pre-mRNA and the remaining sequences are joined together led to a fundamental principle governing biology, known as RNA splicing. The identification stimulated theories for protein diversity, such as alternative splicing, which over time have been realized repeatedly through experiments. Gilbert (1) first proposed the concept of alternative splicing in 1978, which is currently the mechanism that accounts for the discrepancy between the number of protein-coding genes (~25,000) in humans and the >90,000 different proteins that are actually generated (2, 3). The notion of ‘one gene-one RNA-one protein’ is no longer relevant. More than 95% of human genes have been found to undergo splicing in a developmental, tissue-specific or signal transduction-dependent manner (4).

    Constitutive splicing is the process of intron removal and exon ligation of the majority of the exons in the order in which they appear in a gene. Alternative splicing is a deviation from this preferred sequence where certain exons are skipped resulting in various forms of mature mRNA. Weaker splicing signals at alternative splice sites, shorter exon length or higher sequence conservation surrounding orthologous alternative exons influence the exons that are ultimately included in the mature mRNA (5). This process is mediated by a dynamic and flexible macromolecular machine, the spliceosome, which works in a synergistic and antistatic manner (as explained below) (6, 7). Three possible mechanisms, exon shuffling, exonization of transposable elements and constitutively spliced exons, have been proposed for the origin of alternative splicing (8).

    Numerous studies have reiterated the critical and fundamental role of alternative splicing across biological systems (9). The species of higher eukaryotes have been discovered to exhibit a higher proportion of alternatively spliced genes, which is an underlying indication of a prominent role for the mechanism in evolution. Alternative splicing mediates diverse biological processes over the entire life span of organisms, from before birth to death (10, 11). Conserved splicing to species-specific splice variants play a significant functional role in species differentiation and genome evolution (12, 13), as well as in the development of functionally simple to complex tissues with diverse cell types, such as the brain, testis and the immune system. Alternative splicing even participates in RNA processing itself, from pre- to post-transcriptional events.

    Thus, alternative splicing has a role in almost every aspect of protein function, including binding between proteins and ligands, nucleic acids or membranes, localization and enzymatic properties. Taken together, alternative splicing is a central element in gene expression (14).

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    2. Molecular mechanisms of alternative spicing

    Systematic analyses of ESTs and microarray data have so far revealed seven main types of alternative splicing (12) (Fig. 1). The most prevalent pattern (~30%) is the cassette-type alternative exon (exon skipping) in vertebrates and invertebrates (Fig. 1C), while in lower metazoans, it is intron retention (Fig. 1F) (15). Intron retention in human transcripts is positioned primarily in the untranslated regions (UTRs) (16) and has been associated with weaker splice sites, short intron length and the regulation of cis-regulatory elements (17).

    Source : www.ncbi.nlm.nih.gov

    BS 161 HW 25 (4/23 Lecture) Flashcards

    Start studying BS 161 HW 25 (4/23 Lecture). Learn vocabulary, terms, and more with flashcards, games, and other study tools.

    BS 161 HW 25 (4/23 Lecture)

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    Many genes have multiple enhancer sequences. The multiple enhancer sequences allow multiple:

    A) options for RNA editing of the RNA transcript.

    B) transcription factors to control gene expression.

    C) options for alternative splicing of the RNA transcript.

    D) None of the answer options is correct.

    E) proteins to be made from the same protein-coding gene.

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    B) transcription factors to control gene expression.

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    Enhancer sequences are bound by:

    A) histone-modifying complexes.

    B) RNA splicing complexes.

    C) transcription factors.

    D) RNA editing complexes.

    E) cytosine methylation enzymes.

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    C) transcription factors.

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    1/15 Created by nadyaherfi

    Terms in this set (15)

    Many genes have multiple enhancer sequences. The multiple enhancer sequences allow multiple:

    A) options for RNA editing of the RNA transcript.

    B) transcription factors to control gene expression.

    C) options for alternative splicing of the RNA transcript.

    D) None of the answer options is correct.

    E) proteins to be made from the same protein-coding gene.

    B) transcription factors to control gene expression.

    Enhancer sequences are bound by:

    A) histone-modifying complexes.

    B) RNA splicing complexes.

    C) transcription factors.

    D) RNA editing complexes.

    E) cytosine methylation enzymes.

    C) transcription factors.

    Combinatorial control refers to a regulatory mechanism in which:

    A) transcription requires a specific combination of transcription factors.

    B) each alternatively spliced transcript has a different combination of exons.

    C) transcription is initiated by a combination of sites in the promoter.

    D) transcription is terminated by a combination of sites in the terminator.

    E) None of the answer options is correct.

    A) transcription requires a specific combination of transcription factors.

    A single gene can produce different proteins.

    A) False B) True B) True

    Alternative splicing may be considered a mechanism of gene regulation because it:

    A) results in DNA rearrangements.

    B) enhances RNA editing.

    C) results in different protein products.

    D) is mutagenic.

    C) results in different protein products.

    The human body contains approximately 200 major cell types. They look and function differently from one another because each:

    A) expresses the same set of genes, but in different orders at different times.

    B) expresses a different set of genes.

    C) has a slightly different genome and each expresses a different set of genes.

    D) has a slightly different genome.

    B) expresses a different set of genes.

    A cell could potentially regulate transcription by adjusting the number and kinds of: (Select all that apply.)

    -general transcription factors present.

    -regulatory transcription factors present.

    -components of the RNA polymerase complex present.

    -general transcription factors present.

    -regulatory transcription factors present.

    -components of the RNA polymerase complex present.

    Regulatory transcription factors: (Select all that apply.)

    -bind to DNA sequences in or near gene enhancers.

    -recruit the components of the general transcriptional factors.

    -recruit the components of the RNA polymerase complex.

    -bind to DNA sequences in or near gene enhancers.

    -recruit the components of the general transcriptional factors.

    The process by which a single primary RNA transcript is used to make multiple proteins is called:

    A) alternative splicing.

    B) regulatory splicing.

    C) polymerization control.

    D) combinatorial control.

    E) translational control.

    A) alternative splicing.

    Which one of the following statements about gene regulation is INCORRECT?

    A) Gene regulation occurs only in prokaryotes.

    B) Gene regulation occurs at the post-translational level.

    C) Gene regulation occurs at the level of transcription.

    D) Gene regulation occurs at the level of the chromosome.

    E) Gene regulation occurs at the translational level.

    A) Gene regulation occurs only in prokaryotes.

    Gene regulation in multicellular organisms leads to differential gene expression and specialized cell functions.

    A) True B) False A) True

    Insulin is needed to regulate sugar levels in the blood. While every cell in the body contains genes for the production of insulin, it is only produced by a specialized subset of cells in the pancreas. Therefore:

    A) insulin production is not regulated because the genes for it are present in every cell.

    B) the genes for insulin production must be mutated except in the specialized cells of the pancreas.

    C) only the specialized cells of the pancreas have functional genes for insulin production.

    D) there must be mechanisms of gene regulation that promote insulin expression in the specialized pancreatic cells and prevent insulin expression in all other cells.

    E) every cell must regulate its own sugar production.

    D) there must be mechanisms of gene regulation that promote insulin expression in the specialized pancreatic cells and prevent insulin expression in all other cells.

    Source : quizlet.com

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