Exploring the Diverse Functional and Regulatory Consequences of Alternative Splicing in Development and Disease

Alternative splicing is a fundamental mechanism of eukaryotic RNA regulation that increases the transcriptomic and proteomic complexity within an organism. Moreover, alternative splicing provides a framework for generating unique yet complex tissue- and cell type-specific gene expression profiles, despite using a limited number of genes. Recent efforts to understand the negative consequences of aberrant splicing have increased our understanding of developmental and neurodegenerative diseases such as spinal muscular atrophy, frontotemporal dementia and Parkinsonism linked to chromosome 17, myotonic dystrophy, and amyotrophic lateral sclerosis. Moreover, these studies have led to the development of innovative therapeutic treatments for diseases caused by aberrant splicing, also known as spliceopathies. Despite this, a paucity of information exists on the physiological roles and specific functions of distinct transcript spliceforms for a given gene. Here, we will highlight work that has specifically explored the distinct functions of protein-coding spliceforms during development. Moreover, we will discuss the use of alternative splicing of noncoding exons to regulate the stability and localization of RNA transcripts.

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Molecular Heterogeneity of Multiple Myeloma: Pathogenesis, Prognosis, and Therapeutic Implications

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.8435 ◽

2011 ◽

Vol 29 (14) ◽

pp. 1893-1897 ◽

Cited By ~ 42

Author(s):

Avet-Loiseau Hervé ◽

Magrangeas Florence ◽

Moreau Philippe ◽

Attal Michel ◽

Facon Thierry ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Chromosome 17 ◽

Comparative Genomic ◽

Specific Gene ◽

Molecular Heterogeneity ◽

Significant Heterogeneity ◽

Hodgkin's Lymphomas

Multiple myeloma (MM) is characterized by a significant heterogeneity at the molecular level. The first level is the chromosomal one. Although cytogenetics is difficult to assess in MM, patients can be divided into two categories: hyperdiploidy and non-hyperdiploidy (about half in each group). Using molecular cytogenetic techniques, several subgroups of patients are identified, particularly on the basis of 14q32 translocations. This chromosomal heterogeneity is confirmed by genomic techniques (gene expression profiling or single nucleotide polymorphism/comparative genomic hybridization arrays). Unsupervised analyses of gene expression profiles identified several subgroups of patients, essentially on the basis of chromosomal abnormalities such as hyperdiploidy or 14q32 translocations. However, these analyses failed to separate MM into subentities, which could lead to specific therapeutic approaches, as is the case for non-Hodgkin's lymphomas. Nevertheless, these chromosomal/genomic data can be used for prognostication of patients. Specific chromosomal changes, such as loss of the short arm of chromosome 17, or specific gene expression profiles clearly identify patients with short survival. No molecular change so far has been associated with long survival or even cure, probably because of the short follow-up observed in all studies. So far, it is unclear how to use this massive amount of data to treat patients. Because of the complex and heterogeneous picture of the molecular profiles, it is unexpected that targeted therapies might play a role in MM. The only recognized indication is to propose bortezomib-based approaches for the treatment of patients displaying the translocation t(4;14).

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Faculty Opinions recommendation of Ketamine and Imipramine Reverse Transcriptional Signatures of Susceptibility and Induce Resilience-Specific Gene Expression Profiles.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726695455.793533096 ◽

2017 ◽

Author(s):

E Ronald de Kloet ◽

Lisa van Weert ◽

Onno Meijer

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Specific Gene Expression

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Convergent evolution of venom gland transcriptomes across Metazoa

10.1101/2021.07.04.451048 ◽

2021 ◽

Author(s):

Giulia Zancolli ◽

Maarten Reijnders ◽

Robert Waterhouse ◽

Marc Robinson-Rechavi

Keyword(s):

Gene Expression ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Venom Gland ◽

Bioactive Molecules ◽

Specific Gene ◽

Animal Kingdom ◽

Venom Glands

Animals have repeatedly evolved specialized organs and anatomical structures to produce and deliver a cocktail of potent bioactive molecules to subdue prey or predators: venom. This makes it one of the most widespread convergent functions in the animal kingdom. Whether animals have adopted the same genetic toolkit to evolved venom systems is a fascinating question that still eludes us. Here, we performed the first comparative analysis of venom gland transcriptomes from 20 venomous species spanning the main Metazoan lineages, to test whether different animals have independently adopted similar molecular mechanisms to perform the same function. We found a strong convergence in gene expression profiles, with venom glands being more similar to each other than to any other tissue from the same species, and their differences closely mirroring the species phylogeny. Although venom glands secrete some of the fastest evolving molecules (toxins), their gene expression does not evolve faster than evolutionarily older tissues. We found 15 venom gland specific gene modules enriched in endoplasmic reticulum stress and unfolded protein response pathways, indicating that animals have independently adopted stress response mechanisms to cope with mass production of toxins. This, in turns, activates regulatory networks for epithelial development, cell turnover and maintenance which seem composed of both convergent and lineage-specific factors, possibly reflecting the different developmental origins of venom glands. This study represents the first step towards an understanding of the molecular mechanisms underlying the repeated evolution of one of the most successful adaptive traits in the animal kingdom.

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Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL

Blood ◽

10.1182/blood.2020009404 ◽

2021 ◽

Author(s):

Anja Schmitt ◽

Wendan Xu ◽

Philip Bucher ◽

Melanie Grimm ◽

Martina Konantz ◽

...

Keyword(s):

Cell Death ◽

B Cell ◽

Expression Profiles ◽

Therapeutic Option ◽

Gene Expression Profiles ◽

B Cell Lymphoma ◽

Dimethyl Fumarate ◽

Specific Gene ◽

Molecular Heterogeneity ◽

Stat3 Signaling

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a major therapeutic challenge. DLBCL can be classified into at least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad anti-tumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and JAK kinases. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.

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Biophysical Techniques for Target Validation and Drug Discovery in Transcription-Targeted Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21072301 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2301 ◽

Cited By ~ 3

Author(s):

Mehdi Moustaqil ◽

Yann Gambin ◽

Emma Sierecki

Keyword(s):

Drug Discovery ◽

Therapeutic Strategy ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Attractive Alternative ◽

Specific Gene ◽

Pharmaceutical Companies ◽

Biochemical Activity ◽

Biophysical Techniques ◽

And Personalized Medicine

In the post-genome era, pathologies become associated with specific gene expression profiles and defined molecular lesions can be identified. The traditional therapeutic strategy is to block the identified aberrant biochemical activity. However, an attractive alternative could aim at antagonizing key transcriptional events underlying the pathogenesis, thereby blocking the consequences of a disorder, irrespective of the original biochemical nature. This approach, called transcription therapy, is now rendered possible by major advances in biophysical technologies. In the last two decades, techniques have evolved to become key components of drug discovery platforms, within pharmaceutical companies as well as academic laboratories. This review outlines the current biophysical strategies for transcription manipulation and provides examples of successful applications. It also provides insights into the future development of biophysical methods in drug discovery and personalized medicine.

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In Vivo mRNA Profiling of Uropathogenic Escherichia coli from Diverse Phylogroups Reveals Common and Group-Specific Gene Expression Profiles

mBio ◽

10.1128/mbio.01075-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 39

Author(s):

Piotr Bielecki ◽

Uthayakumar Muthukumarasamy ◽

Denitsa Eckweiler ◽

Agata Bielecka ◽

Sarah Pohl ◽

...

Keyword(s):

Gene Expression ◽

Escherichia Coli ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Specific Gene ◽

Content Type ◽

E Coli ◽

Human Host ◽

Tract Infections

ABSTRACTmRNA profiling of pathogens during the course of human infections gives detailed information on the expression levels of relevant genes that drive pathogenicity and adaptation and at the same time allows for the delineation of phylogenetic relatedness of pathogens that cause specific diseases. In this study, we used mRNA sequencing to acquire information on the expression ofEscherichia colipathogenicity genes during urinary tract infections (UTI) in humans and to assign the UTI-associatedE. coliisolates to different phylogenetic groups. Whereas thein vivogene expression profiles of the majority of genes were conserved among 21E. colistrains in the urine of elderly patients suffering from an acute UTI, the specific gene expression profiles of the flexible genomes was diverse and reflected phylogenetic relationships. Furthermore, genes transcribedin vivorelative to laboratory media included well-described virulence factors, small regulatory RNAs, as well as genes not previously linked to bacterial virulence. Knowledge on relevant transcriptional responses that drive pathogenicity and adaptation of isolates to the human host might lead to the introduction of a virulence typing strategy into clinical microbiology, potentially facilitating management and prevention of the disease.IMPORTANCEUrinary tract infections (UTI) are very common; at least half of all women experience UTI, most of which are caused by pathogenicEscherichia colistrains. In this study, we applied massive parallel cDNA sequencing (RNA-seq) to provide unbiased, deep, and accurate insight into the nature and the dimension of the uropathogenicE. coligene expression profile during an acute UTI within the human host. This work was undertaken to identify key players in physiological adaptation processes and, hence, potential targets for new infection prevention and therapy interventions specifically aimed at sabotaging bacterial adaptation to the human host.

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Establishment of Cell Lines That Exhibit Correct Ontogenic Stage-Specific Gene Expression Profiles From Tissues of Yeast Artificial Chromosome Transgenic Mice Using Chemically Induced Growth Signals

YAC Protocols ◽

10.1385/1-59745-158-4:163 ◽

2006 ◽

pp. 163-174

Author(s):

C. Anthony Blau ◽

Kenneth R. Peterson

Keyword(s):

Gene Expression ◽

Transgenic Mice ◽

Cell Lines ◽

Yeast Artificial Chromosome ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Artificial Chromosome ◽

Specific Gene ◽

Specific Gene Expression ◽

Chemically Induced

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Gene Expression Profiles Controlled by the Alternative Splicing Factor Nova2 in Endothelial Cells

Cells ◽

10.3390/cells8121498 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1498 ◽

Cited By ~ 3

Author(s):

Elisa Belloni ◽

Anna Di Matteo ◽

Davide Pradella ◽

Margherita Vacca ◽

Christopher D. R. Wyatt ◽

...

Keyword(s):

Alternative Splicing ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Protein Isoforms ◽

Peroxisome Proliferator ◽

Bioinformatics Analyses ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Significant Enrichment ◽

Steady State Levels

Alternative splicing (AS) plays an important role in expanding the complexity of the human genome through the production of specialized proteins regulating organ development and physiological functions, as well as contributing to several pathological conditions. How AS programs impact on the signaling pathways controlling endothelial cell (EC) functions and vascular development is largely unknown. Here we identified, through RNA-seq, changes in mRNA steady-state levels in ECs caused by the neuro-oncological ventral antigen 2 (Nova2), a key AS regulator of the vascular morphogenesis. Bioinformatics analyses identified significant enrichment for genes regulated by peroxisome proliferator-activated receptor-gamma (Ppar-γ) and E2F1 transcription factors. We also showed that Nova2 in ECs controlled the AS profiles of Ppar-γ and E2F dimerization partner 2 (Tfdp2), thus generating different protein isoforms with distinct function (Ppar-γ) or subcellular localization (Tfdp2). Collectively, our results supported a mechanism whereby Nova2 integrated splicing decisions in order to regulate Ppar-γ and E2F1 activities. Our data added a layer to the sequential series of events controlled by Nova2 in ECs to orchestrate vascular biology.

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