Modulation of Alternative Splicing with Chemical Compounds in New Therapeutics for Human Diseases

2015 ◽  
Vol 10 (4) ◽  
pp. 914-924 ◽  
Author(s):  
Kenji Ohe ◽  
Masatoshi Hagiwara
Keyword(s):  
Alternative Splicing ◽  
Chemical Compounds ◽  
Human Diseases

scholarly journals When small RNAs become smaller: non - canonical functions of snoRNAs and their derivatives

2017 ◽  
Vol 63 (4) ◽  
Author(s):  
Anna Maria Mleczko ◽  
Kamilla Bąkowska-Żywicka
Keyword(s):  
Alternative Splicing ◽  
Small Rnas ◽  
Metabolic Stress ◽  
Full Length ◽  
Human Diseases ◽  
Cajal Bodies ◽  
Prader Willi Syndrome ◽  
Small Nucleolar Rnas ◽  
Stress Regulation ◽  
Nucleolar Rnas

Small nucleolar RNAs (snoRNAs) are molecules placed in the cell nucleolus and in Cajal bodies. Many scientific reports clearly show that snoRNAs are not only responsible for modifications of other RNAs but also possess multiple other functions such as metabolic stress regulation or modulation of alternative splicing. Full-length snoRNAs as well as small RNAs derived from snoRNAs have been implied in human diseases such as cancer or Prader – Willi Syndrome.  In this review we would like to describe these non – canonical roles of snoRNAs and their derivatives  with the emphasis on their role in human diseases. 

COMPARATIVE ANALYSIS OF DISEASE-ASSOCIATED MUTATIONS IN THE CODING REGIONS OF ALTERNATIVELY AND CONSTITUTIVELY SPLICED HUMAN GENES

2008 ◽  
Vol 16 (02) ◽  
pp. 241-253
Author(s):  
QIANLI HUANG ◽  
YONG LI ◽  
JESSE LI-LING ◽  
HUIFANG HUANG ◽  
XUEPING CHEN ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Codon Usage ◽  
Codon Usage Bias ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Human Diseases ◽  
Disease Genes ◽  
Single Mutation ◽  
Coding Regions ◽  
Human Disease Genes

To better understand the evolutionary and molecular mechanisms of alternative splicing causing human diseases, we have systematically compared the pattern, the distribution and the density of disease-associated mutations as well as the influence of codon usage bias on the single mutation between alternatively and constitutively spliced genes through analysis of the large datasets from human disease genes. The results indicated that: 1. The most common pattern of single mutation in alternatively and constitutively spliced genes are, respectively, C/T (25.17%), (22.81%) and G/A (21.54%), (22.73%), suggesting that the two types of disease genes are prone to C → T and G → A mutations. 2. There is an overall preponderance for transitions over transversions in alternatively (62.88% versus 37.12%) and constitutively (64.41% versus 35.59%) spliced disease genes. 3. For the second base of codons, there exist significant differences in transitions and transversions between the two types of genes. 4. Our data indicated that the single mutation tends to occur preferentially when the upstream neighboring-nucleotide is C or G in human disease genes. 5. Codon usage bias and synonymous codon usage have great influence on the single mutation in both alternatively and constitutively spliced genes. The GC content and gene length also have very evident influence on such mutations. Our results seem to imply that disease-associated mutations within the coding regions of alternatively spliced human disease genes have different mechanisms from constitutively spliced genes. Such findings may facilitate understanding the molecular mechanism of alternative splicing causing human diseases, and the development of gene therapies for such diseases.

scholarly journals Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Sean M. Cascarina ◽  
Eric D. Ross
Keyword(s):  
Alternative Splicing ◽  
Neurodegenerative Disorders ◽  
Protein Sequence ◽  
Human Disease ◽  
Large Scale ◽  
Sequence Variation ◽  
Human Diseases ◽  
Transcriptional Level ◽  
Sequence Variants ◽  
Aggregation Propensity

Abstract Background Impaired proteostatic regulation of proteins with prion-like domains (PrLDs) is associated with a variety of human diseases including neurodegenerative disorders, myopathies, and certain forms of cancer. For many of these disorders, current models suggest a prion-like molecular mechanism of disease, whereby proteins aggregate and spread to neighboring cells in an infectious manner. The development of prion prediction algorithms has facilitated the large-scale identification of PrLDs among “reference” proteomes for various organisms. However, the degree to which intraspecies protein sequence diversity influences predicted prion propensity has not been systematically examined. Results Here, we explore protein sequence variation introduced at genetic, post-transcriptional, and post-translational levels, and its influence on predicted aggregation propensity for human PrLDs. We find that sequence variation is relatively common among PrLDs and in some cases can result in relatively large differences in predicted prion propensity. Sequence variation introduced at the post-transcriptional level (via alternative splicing) also commonly affects predicted aggregation propensity, often by direct inclusion or exclusion of a PrLD. Finally, analysis of a database of sequence variants associated with human disease reveals a number of mutations within PrLDs that are predicted to increase prion propensity. Conclusions Our analyses expand the list of candidate human PrLDs, quantitatively estimate the effects of sequence variation on the aggregation propensity of PrLDs, and suggest the involvement of prion-like mechanisms in additional human diseases.

scholarly journals Population epigenetics, ecotoxicology and human diseases

2012 ◽  
Vol 10 (4) ◽  
pp. 14-28
Author(s):  
Eugene L Patkin ◽  
Henry A Sofronov
Keyword(s):  
Environmental Factors ◽  
Chemical Compounds ◽  
External Factors ◽  
Human Diseases ◽  
Epigenetic Mechanisms ◽  
Epigenetic Variability ◽  
Current State ◽  
Population Epigenetics

The review critically examines the current state of population epigenetics. Possible mechanisms of intergenerational inheritance of epigenetic and epigenomic modifications as a condition of population epigenetics reality are examined. Special attention is paid to the role of external factors, including diet and various chemical compounds as modulators of the epigenome, and the possible inheritance of epigenetic variability characteristics under the influence of such environmental factors. The role of epigenetic mechanisms in the etiology and susceptibility to complex human diseases is considered.

scholarly journals Phylostratigraphic analysis of gene networks of human diseases

2021 ◽  
Vol 25 (1) ◽  
pp. 46-56
Author(s):  
Z. S. Mustafin ◽  
S. A. Lashin ◽  
Yu. G. Matushkin
Keyword(s):  
Genetic Variability ◽  
Gene Networks ◽  
Gene Evolution ◽  
Chemical Compounds ◽  
Human Diseases ◽  
Orthologous Group ◽  
Stabilizing Selection ◽  
Gene Origin ◽  
Reliable Correlation ◽  
Time Of Origin

Phylostratigraphic analysis is an approach to the study of gene evolution that makes it possible to determine the time of the origin of genes by analyzing their orthologous groups. The age of a gene belonging to an orthologous group is def ined as the age of the most recent ancestor of all species represented in that group. Such an analysis can reveal important stages in the evolution of both the organism as a whole and groups of functionally related genes, in particular gene networks. In addition to investigating the time of origin of a gene, the level of its genetic variability and what type of selection the gene is subject to in relation to the most closely related organisms is studied. Using the Orthoscape application, gene networks from the KEGG Pathway, Human Diseases database describing various human diseases were analyzed. It was shown that the majority of genes described in gene networks are under stabilizing selection and a high reliable correlation was found between the time of gene origin and the level of genetic variability: the younger the gene, the higher the level of its variability is. It was also shown that among the gene networks analyzed, the highest proportion of evolutionarily young genes was found in the networks associated with diseases of the immune system (65 %), and the highest proportion of evolutionarily ancient genes was found in the networks responsible for the formation of human dependence on substances that cause addiction to chemical compounds (88 %); gene networks responsible for the development of infectious diseases caused by parasites are signif icantly enriched for evolutionarily young genes, and gene networks responsible for the development of specif ic types of cancer are signif icantly enriched for evolutionarily ancient genes.

scholarly journals Alternative Splicing as a Therapeutic Target for Human Diseases

2009 ◽  
pp. 127-144 ◽  
Author(s):  
Kenneth J. Dery ◽  
Veronica Gusti ◽  
Shikha Gaur ◽  
John E. Shively ◽  
Yun Yen ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Therapeutic Target ◽  
Human Diseases

My road to alternative splicing control: from simple paths to loops and interconnections

2015 ◽  
Vol 93 (3) ◽  
pp. 171-179 ◽  
Author(s):  
Benoit Chabot
Keyword(s):  
Dna Damage ◽  
Alternative Splicing ◽  
Biological System ◽  
Splice Variants ◽  
Human Diseases ◽  
Functional Importance ◽  
Basic Principles ◽  
Simple Paths ◽  
The Impact

With the functional importance of alternative splicing being validated in nearly every mammalian biological system and implicated in many human diseases, it is now crucial to identify the molecular programs that control the production of splice variants. In this article, I will survey how our knowledge of the basic principles of alternative splicing control evolved over the last 25 years. I will also describe how investigation of the splicing control of an apoptotic regulator led us to identify novel effectors and revealed the existence of converging pathways linking splicing decisions to DNA damage. Finally, I will review how our efforts at developing tools designed to monitor and redirect splicing helped assess the impact of misregulated splicing in cancer.

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