scholarly journals Epigenetics of Myotonic Dystrophies: A Minireview

2021 ◽  
Vol 22 (22) ◽  
pp. 12594
Author(s):  
Virginia Veronica Visconti ◽  
Federica Centofanti ◽  
Simona Fittipaldi ◽  
Elisa Macrì ◽  
Giuseppe Novelli ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Cytosine Methylation ◽  
Therapeutic Interventions ◽  
Prevailing Paradigm ◽  
Epigenetic Biomarkers ◽  
Repeat Expansions ◽  
Cctg Repeat ◽  
In Trans ◽  
Toxic Rna ◽  
Available Information

Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an in trans toxic RNA mechanism, triggered by untranslated CTG and CCTG repeat expansions in the DMPK and CNBP genes for DM1 and DM2, respectively. Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of both diseases. In this review, we discuss the available information on epigenetic mechanisms that could contribute to the DMs outcome and progression. Changes in DNA cytosine methylation, chromatin remodeling and expression of regulatory noncoding RNAs are described, with the intent of depicting an epigenetic signature of DMs. Epigenetic biomarkers have a strong potential for clinical application since they could be used as targets for therapeutic interventions avoiding changes in DNA sequences. Moreover, understanding their clinical significance may serve as a diagnostic indicator in genetic counselling in order to improve genotype–phenotype correlations in DM patients.

scholarly journals Epigenetic Alterations in Muscular Disorders

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Chiara Lanzuolo
Keyword(s):  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Neuromuscular Disorders ◽  
Expression Patterns ◽  
Normal Subjects ◽  
Therapeutic Interventions ◽  
Epigenetic Mechanisms ◽  
Muscular Disorders ◽  
Quality Stability ◽  
Available Information

Epigenetic mechanisms, acting via chromatin organization, fix in time and space different transcriptional programs and contribute to the quality, stability, and heritability of cell-specific transcription programs. In the last years, great advances have been made in our understanding of mechanisms by which this occurs in normal subjects. However, only a small part of the complete picture has been revealed. Abnormal gene expression patterns are often implicated in the development of different diseases, and thus epigenetic studies from patients promise to fill an important lack of knowledge, deciphering aberrant molecular mechanisms at the basis of pathogenesis and diseases progression. The identification of epigenetic modifications that could be used as targets for therapeutic interventions could be particularly timely in the light of pharmacologically reversion of pathological perturbations, avoiding changes in DNA sequences. Here I discuss the available information on epigenetic mechanisms that, altered in neuromuscular disorders, could contribute to the progression of the disease.

scholarly journals Minidumbbell structures formed by ATTCT pentanucleotide repeats in spinocerebellar ataxia type 10

2020 ◽  
Author(s):  
Pei Guo ◽  
Sik Lok Lam
Keyword(s):  
Spinocerebellar Ataxia ◽  
Dna Polymerase ◽  
Dna Sequences ◽  
Solution Structure ◽  
Large Scale ◽  
Genetic Disorder ◽  
Spinocerebellar Ataxia Type ◽  
Klenow Fragment ◽  
Repeat Expansions

Abstract Spinocerebellar ataxia type 10 (SCA10) is a progressive genetic disorder caused by ATTCT pentanucleotide repeat expansions in intron 9 of the ATXN10 gene. ATTCT repeats have been reported to form unwound secondary structures which are likely linked to large-scale repeat expansions. In this study, we performed high-resolution nuclear magnetic resonance spectroscopic investigations on DNA sequences containing two to five ATTCT repeats. Strikingly, we found the first two repeats of all these sequences well folded into highly compact minidumbbell (MDB) structures. The 3D solution structure of the sequence containing two ATTCT repeats was successfully determined, revealing the MDB comprises a regular TTCTA and a quasi TTCT/A pentaloops with extensive stabilizing loop-loop interactions. We further carried out in vitro primer extension assays to examine if the MDB formed in the primer could escape from the proofreading function of DNA polymerase. Results showed that when the MDB was formed at 5-bp or farther away from the priming site, it was able to escape from the proofreading by Klenow fragment of DNA polymerase I and thus retained in the primer. The intriguing structural findings bring about new insights into the origin of genetic instability in SCA10.

Unusual structures of CCTG repeats and their participation in repeat expansion

2016 ◽  
Vol 7 (5-6) ◽  
pp. 331-340 ◽  
Author(s):  
Pei Guo ◽  
Sik Lok Lam
Keyword(s):  
Conformational Dynamics ◽  
Structural Diversity ◽  
Repeat Expansion ◽  
Nucleic Acid Binding ◽  
Myotonic Dystrophy Type 2 ◽  
Unusual Structure ◽  
Intron 1 ◽  
Repeat Expansions ◽  
Cctg Repeat ◽  
The One

AbstractCCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instability in CCTG repeats remain elusive. In recent years, CCTG repeats have been found to form various types of unusual secondary structures including mini-dumbbell (MDB), hairpin and dumbbell, revealing that there is a high structural diversity in CCTG repeats intrinsically. Upon strand slippage, the formation of unusual structures in the nascent strand during DNA replication has been proposed to be the culprit of CCTG repeat expansions. On the one hand, the thermodynamic stability, size, and conformational dynamics of these unusual structures affect the propensity of strand slippage. On the other hand, these structural properties determine whether the unusual structure can successfully escape from DNA repair. In this short overview, we first summarize the recent advances in elucidating the solution structures of CCTG repeats. We then discuss the potential pathways by which these unusual structures bring about variable sizes of repeat expansion, high strand slippage propensity and efficient repair escape.

scholarly journals New Perspectives on Innovative Drug Discovery: An Overview

2010 ◽  
Vol 13 (3) ◽  
pp. 450 ◽  
Author(s):  
Si Yuan Pan ◽  
Shan Pan ◽  
Zhi-Ling Yu ◽  
Dik-Lung Ma ◽  
Si-Bao Chen ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Wide Spectrum ◽  
Therapeutic Interventions ◽  
Biomedical Science ◽  
Innovative Drug ◽  
Alternative Medicines ◽  
Traditional Remedies ◽  
Available Information ◽  
Rate Of Success ◽  
Total Sales

Despite advances in technology, drug discovery is still a lengthy, expensive, difficult, and inefficient process, with a low rate of success. Today, advances in biomedical science have brought about great strides in therapeutic interventions for a wide spectrum of diseases. The advent of biochemical techniques and cutting-edge bio/chemical technologies has made available a plethora of practical approaches to drug screening and design. In 2010, the total sales of the global pharmaceutical market will reach 600 billion US dollars and expand to over 975 billion dollars by 2013. The aim of this review is to summarize available information on contemporary approaches and strategies in the discovery of novel therapeutic agents, especially from the complementary and alternative medicines, including natural products and traditional remedies such as Chinese herbal medicine.

scholarly journals COELENTERATE TOXINS, ITS PHARMACEUTICAL AND THERAPEUTIC EFFECTS

2021 ◽  
pp. 11-19
Author(s):  
SIMRAN SHARMA ◽  
RAVI KANT UPADHYAY
Keyword(s):  
Skeletal Muscles ◽  
Therapeutic Interventions ◽  
Therapeutic Effects ◽  
Human Beings ◽  
Venom Toxin ◽  
Immunological Reactions ◽  
Parasitic Activity ◽  
Species Specific ◽  
Available Information ◽  
Diverse Biological Activity

Present review article emphasizes species specific coelenterate toxins, its pharmaceutical and therapeutic effects. Most of the coelenterates inflict venom accidently by using nematocysts found on arms. These animals very quickly do massive and multiple inflictions of venom which causes cardiotoxicity that leads to the death of human beings. Coelenterate venom toxin groups differ in their composition and show diverse biological activity i.e. cytolytic or neurotoxic, hemolytic, anti-parasitic activity, α-amylase inhibitor activity, and analgesic activity anti-cancerous and antitumor activity, anti-inflammatory and antimicrobial activity. Coelenterate venom initiates toxic and immunological reactions exert their effects by modifying the properties of the ion channels involved in action potential generation in nerve, heart, and skeletal muscles. This article suggests available information, on coelenterate toxins could be used to develop potential therapeutic interventions for various human diseases and disorders.

scholarly journals Deoxyribonucleic acid methylation and chromatin organization in Tetrahymena thermophila.

1981 ◽  
Vol 1 (7) ◽  
pp. 600-608 ◽  
Author(s):  
K Pratt ◽  
S Hattman
Keyword(s):  
Dna Replication ◽  
Dna Sequence ◽  
Dna Sequences ◽  
Cytosine Methylation ◽  
Deoxyribonucleic Acid ◽  
Tetrahymena Thermophila ◽  
Staphylococcal Nuclease ◽  
Chromatin Organization ◽  
Deoxyribonuclease I ◽  
Cell Biol

Deoxyribonucleic acid (DNA) of the transcriptionally active macronucleus of Tetrahymena thermophila is methylated at the N6 position of adenine to produce methyladenine (MeAde); approximately 1 in every 125 adenine residues (0.8 mol%) is methylated. Transcriptionally inert micronuclear DNA is not methylated (< or = 0.01 mol% MeAde; M. A. Gorovsky, S. Hattman, and G. L. Pleger, J. Cell Biol. 56:697-701, 1973). There is no detectable cytosine methylation in macronuclei in Tetrahymena DNA (< or = 0.01 mol% 5-methylcytosine). MeAde-containing DNA sequences in macronuclei are preferentially digested by both staphylococcal nuclease and pancreatic deoxyribonuclease I. In contrast, there is no preferential release of MeAde during digestion of purified DNA. These results indicate that MeAde residues are predominantly located in "linker DNA" and perhaps have a function in transcription. Pulse-chase studies showed that labeled MeAde remains preferentially in linker DNA during subsequent rounds of DNA replication; i.e., there is little, if any, movement of nucleosomes during chromatin replication. This implies that nucleosomes may be phased with respect to DNA sequence.

A Divorce Transition Model

1992 ◽  
Vol 70 (1) ◽  
pp. 155-160 ◽  
Author(s):  
Nina M. Steefel
Keyword(s):  
Transition Theory ◽  
Therapeutic Interventions ◽  
Transition Model ◽  
Comprehensive Model ◽  
Research Results ◽  
Available Information

A comprehensive model of divorce experience can provide a useful framework for organizing available information, for incorporating research results, and for planning therapeutic interventions with divorcing clients. The concept that the experience of divorce can be thought of as a cluster of specific small divorces is combined with transition theory to form such a model. Examples of application for practice are provided.

scholarly journals Aurintricarboxylic Acid Decreases RNA Toxicity in a C. elegans Model of Repeat Expansions

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 910
Author(s):  
Maya Braun ◽  
Shachar Shoshani ◽  
Anna Mellul-Shtern ◽  
Yuval Tabach
Keyword(s):  
Rna Interference ◽  
Tandem Repeats ◽  
Drug Repositioning ◽  
Aurintricarboxylic Acid ◽  
Rna Toxicity ◽  
C Elegans ◽  
Disease Phenotypes ◽  
Repeat Expansions ◽  
Toxic Rna

Pathologic expansions of DNA nucleotide tandem repeats may generate toxic RNA that triggers disease phenotypes. RNA toxicity is the hallmark of multiple expansion repeat disorders, including myotonic dystrophy type 1 (DM1). To date, there are no available disease-modifying therapies for DM1. Our aim was to use drug repositioning to ameliorate the phenotype of affected individuals in a nematode model of DM1. As the RNA interference pathway plays a key role in mediating RNA toxicity, we investigated the effect of aurintricarboxylic acid. We demonstrated that by perturbing the RNA interference machinery using aurintricarboxylic acid, we could annihilate the RNA toxicity and ameliorate the phenotype. As our approach targets a universal disease mechanism, it is potentially relevant for more expansion repeat disorders.

scholarly journals Unveiling DNA algorithms: satellite DNA sequences as iterable objects. A computational model.

2022 ◽  
Author(s):  
Marco Regolini
Keyword(s):  
Dna Sequences ◽  
Satellite Dna ◽  
Computational Models ◽  
Cytosine Methylation ◽  
Somatic Cells ◽  
Interspecific Variability ◽  
Cell Divisions ◽  
Epigenetic Marker ◽  
Adult Hermaphrodite ◽  
Second Order Logic

Every adult male of the little roundworm Caenorhabditis elegans is always and invariably comprised of exactly 1031 somatic cells, not one more, not one less; and so it is for the adult hermaphrodite (959 somatic cells); its intestine founder cell (the ‘E’ blastomere), if isolated and cultured, undergoes the same number of divisions as in the whole embryo (Robertson et al., 2014); the zygote of Drosophila melanogaster executes 13 cycles of asynchronous cell divisions without cellularization: how are these numbers counted? Artificial Intelligence (First and Second Order Logic, Knowledge graph Engineering) infers that, to perform precise stereotypical numbers of asynchronous cell divisions, a nucleic (genomic) counter is indispensable. Made up of tandemly repeated similar monomers, satellite DNA (satDNA) corresponds to iterable objects used in programming. The purpose of this article is to show how satDNA sequences can be iterated over to count a deterministic number of cell divisions: computational models (attached for free download) are introduced that handle DNA repeated sequences as iterable counters and simulate their use in cells through an epigenetic marker (cytosine methylation) as an iterator. SatDNA, because of its propensity to remodel its structure, can also operate as a strong accelerator in the evolution of complex organs and provides a basis to control interspecific variability of shapes.

scholarly journals Molecular Mechanisms in Pentanucleotide Repeat Diseases

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 205
Author(s):  
Joana R. Loureiro ◽  
Ana F. Castro ◽  
Ana S. Figueiredo ◽  
Isabel Silveira
Keyword(s):  
Phase Separation ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Spinocerebellar Ataxias ◽  
Genes Encoding ◽  
Dna Strands ◽  
Repeat Expansions ◽  
Toxic Rna ◽  
Pentanucleotide Repeat

The number of neurodegenerative diseases resulting from repeat expansion has increased extraordinarily in recent years. In several of these pathologies, the repeat can be transcribed in RNA from both DNA strands producing, at least, one toxic RNA repeat that causes neurodegeneration by a complex mechanism. Recently, seven diseases have been found caused by a novel intronic pentanucleotide repeat in distinct genes encoding proteins highly expressed in the cerebellum. These disorders are clinically heterogeneous being characterized by impaired motor function, resulting from ataxia or epilepsy. The role that apparently normal proteins from these mutant genes play in these pathologies is not known. However, recent advances in previously known spinocerebellar ataxias originated by abnormal non-coding pentanucleotide repeats point to a gain of a toxic function by the pathogenic repeat-containing RNA that abnormally forms nuclear foci with RNA-binding proteins. In cells, RNA foci have been shown to be formed by phase separation. Moreover, the field of repeat expansions has lately achieved an extraordinary progress with the discovery that RNA repeats, polyglutamine, and polyalanine proteins are crucial for the formation of nuclear membraneless organelles by phase separation, which is perturbed when they are expanded. This review will cover the amazing advances on repeat diseases.

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