Current Genomics

ISSN: 1389-2029

Current Genomics
Volume 9, Number 8, December 2008

Contents


Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene Pp. 509-516
B. Llamusí and R. Artero
[Abstract] [Full text article]


Systems Behavior: Of Male Courtship, the Nervous System and Beyond in Drosophila Pp. 517-524
B. Dauwalder
[Abstract] [Full text article]


Meta Analysis of Gene Expression Data within and Across Species Pp. 525-534
A.C. Fierro, F. Vandenbussche, K. Engelen, Y. Van de Peer and K. Marchal
[Abstract] [Full text article]


Genomic Instability and Carcinogenesis: An Update Pp. 535-541
W.M. Abdel-Rahman
[Abstract] [Full text article]


Genetics in Osteoarthritis Pp. 542-547
M. Fernández-Moreno, I. Rego, V. Carreira-Garcia and F.J. Blanco
[Abstract] [Full text article]


Periostin as a Heterofunctional Regulator of Cardiac Development and Disease Pp. 548-555
S.J. Conway and J. D. Molkentin
[Abstract] [Full text article]


Alternative Splicing and Tumor Progression Pp. 556-570
C. Ghigna, C. Valacca and G. Biamonti
[Abstract] [Full text article]


Toxicogenomics to Improve Comprehension of the Mechanisms Underlying Responses of In Vitro and In Vivo Systems to Nanomaterials: A Review Pp. 571-585
A. Poma and M.L. Di Giorgio
[Abstract] [Full text article]




Abstracts


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Molecular Effects of the CTG Repeats in Mutant Dystrophia Myotonica Protein Kinase Gene
B. Llamusí and R. Artero

Myotonic Dystrophy type 1 (DM1) is a multi-system disorder characterized by muscle wasting, myotonia, cardiac conduction defects, cataracts, and neuropsychological dysfunction. DM1 is caused by expansion of a CTG repeat in the 3´untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. A body of work demonstrates that DMPK mRNAs containing abnormally expanded CUG repeats are toxic to several cell types. A core mechanism underlying symptoms of DM1 is that mutant DMPK RNA interferes with the developmentally regulated alternative splicing of defined pre-mRNAs. Expanded CUG repeats fold into ds(CUG) hairpins that sequester nuclear proteins including human Muscleblind-like (MBNL) and hnRNP H alternative splicing factors. DM1 cells activate CELF family member CUG-BP1 protein through hyperphosphorylation and stabilization in the cell nucleus. CUG-BP1 and MBNL1 proteins act antagonistically in exon selection in several pre-mRNA transcripts, thus MBNL1 sequestration and increase in nuclear activity of CUG-BP1 both act synergistically to missplice defined transcripts. Mutant DMPK-mediated effect on subcellular localization, and defective phosphorylation of cytoplasmic CUG-BP1, have additionally been linked to defective translation of p21 and MEF2A in DM1, possibly explaining delayed differentiation of DM1 muscle cells. Mutant DMPK transcripts bind and sequester transcription factors such as Specificity protein 1 leading to reduced transcription of selected genes. Recently, transcripts containing long hairpin structures of CUG repeats have been shown to be a Dicer ribonuclease target and Dicer-induced downregulation of the mutant DMPK transcripts triggers silencing effects on RNAs containing long complementary repeats. In summary, mutant DMPK transcripts alter gene transcription, alternative splicing, and translation of specific gene transcripts, and have the ability to trigger gene-specific silencing effects in DM1 cells. Therapies aimed at reversing these gene expression alterations should prove effective ways to treat DM1.


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Systems Behavior: Of Male Courtship, the Nervous System and Beyond in Drosophila
B. Dauwalder

Male courtship in fruit flies is regulated by the same major regulatory genes that also determine general sexual differentiation of the animal. Elaborate genetics has given us insight into the roles of these master genes. These findings have suggested two separate and independent pathways for the regulation of sexual behavior and other aspects of sexual differentiation. Only recently have molecular studies started to look at the downstream effector genes and how they might control sex-specific behavior. These studies have confirmed the essential role of the previously identified male specific products of the fruitless gene in the neuronal circuits in which it is expressed. But there is increasing evidence that a number of non-neuronal tissues and pathways play a pivotal role in modulating this circuit and assuring efficient courtship.


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Meta Analysis of Gene Expression Data within and Across Species
A.C. Fierro, F. Vandenbussche, K. Engelen, Y. Van de Peer and K. Marchal

Since the second half of the 1990s, a large number of genome-wide analyses have been described that study gene expression at the transcript level. To this end, two major strategies have been adopted, a first one relying on hybridization techniques such as microarrays, and a second one based on sequencing techniques such as serial analysis of gene expression (SAGE), cDNA-AFLP, and analysis based on expressed sequence tags (ESTs). Despite both types of profiling experiments becoming routine techniques in many research groups, their application remains costly and laborious. As a result, the number of conditions profiled in individual studies is still relatively small and usually varies from only two to few hundreds of samples for the largest experiments. More and more, scientific journals require the deposit of these high throughput experiments in public databases upon publication. Mining the information present in these databases offers molecular biologists the possibility to view their own small-scale analysis in the light of what is already available. However, so far, the richness of the public information remains largely unexploited. Several obstacles such as the correct association between ESTs and microarray probes with the corresponding gene transcript, the incompleteness and inconsistency in the annotation of experimental conditions, and the lack of standardized experimental protocols to generate gene expression data, all impede the successful mining of these data. Here, we review the potential and difficulties of combining publicly available expression data from respectively EST analyses and microarray experiments. With examples from literature, we show how meta-analysis of expression profiling experiments can be used to study expression behavior in a single organism or between organisms, across a wide range of experimental conditions. We also provide an overview of the methods and tools that can aid molecular biologists in exploiting these public data.


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Genomic Instability and Carcinogenesis: An Update
W.M. Abdel-Rahman

Cancers arise as a result of stepwise accumulation of mutations which may occur at the nucleotide level and/or the gross chromosomal level. Many cancers particularly those of the colon display a form of genomic instability which may facilitate and speed up tumor initiation and development. In few instances, a “mutator mutation” has been clearly implicated in driving the accumulation of other carcinogenic mutations. For example, the post-replicative DNA mismatch repair deficiency results in dramatic increase in insertion/deletion mutations giving rise to the microsatellite instability (MSI) phenotype and may predispose to a spectrum of tumours when it occurs in the germline. Although many sporadic cancers show multiple mutations suggesting unstable genome, the role of this instability in carcinogenesis, as opposed to the power of natural selection, has been a matter of controversy. This review gives an update of the latest data on these issues particularly recent data from genome-wide, high throughput techniques as well as mathematical modelling. Throughout this review, reference will be made to the relevance of genomic instability to the pathogenesis of colorectal carcinoma particularly its hereditary and familial subsets.


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Genetics in Osteoarthritis
M. Fernández-Moreno, I. Rego, V. Carreira-Garcia and F.J. Blanco

Osteoarthritis is a degenerative articular disease with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. Despite the multifactorial nature of this pathology, from the 50’s it´s known that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidate genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this disease are not known, however, which seems clear is that expression levels of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthritis.


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Periostin as a Heterofunctional Regulator of Cardiac Development and Disease
S.J. Conway and J. D. Molkentin

Periostin (Postn) is a heterofunctional secreted extracellular matrix (ECM) protein comprised of four fasciclin domains that promotes cellular adhesion and movement, as well as collagen fibrillogenesis. Postn is expressed in unique growth centers during embryonic development where it facilitates epithelial-mesenchymal transition (EMT) of select cell populations undergoing reorganization. In the heart, Postn is expressed in the developing valves, cardiac fibroblasts and in regions of the outflow track. In the adult, Postn expression is specifically induced in areas of tissue injury or areas with ongoing cellular re-organization. In the adult heart Postn is induced in the ventricles following myocardial infarction, pressure overload stimulation, or generalized cardiomyopathy. Here we will review the functional consequences associated with Postn induction in both the developing and adult heart. The majority of data collected to date suggest a common function for Postn in both development and disease as a potent inducible regulator of cellular reorganization and extracellular matrix homeostasis, although some alternate and controversial functions have also been ascribed to Postn, the validity of which will be discussed here.


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Alternative Splicing and Tumor Progression
C. Ghigna, C. Valacca and G. Biamonti

Alternative splicing is a key molecular mechanism for increasing the functional diversity of the eukaryotic proteomes. A large body of experimental data implicates aberrant splicing in various human diseases, including cancer. Both mutations in cis-acting splicing elements and alterations in the expression and/or activity of splicing regulatory factors drastically affect the splicing profile of many cancer-associated genes. In addition, the splicing profile of several cancer-associated genes is altered in particular types of cancer arguing for a direct role of specific splicing isoforms in tumor progression. Deciphering the mechanisms underlying aberrant splicing in cancer may prove crucial to understand how splicing machinery is controlled and integrated with other cellular processes, in particular transcription and signaling pathways. Moreover, the characterization of splicing deregulation in cancer will lead to a better comprehension of malignant transformation. Cancer-associated alternative splicing variants may be new tools for the diagnosis and classification of cancers and could be the targets for innovative therapeutical interventions based on highly selective splicing correction approaches.


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Toxicogenomics to Improve Comprehension of the Mechanisms Underlying Responses of In Vitro and In Vivo Systems to Nanomaterials: A Review
A. Poma and M.L. Di Giorgio

Engineered nanomaterials are commonly defined as materials with at least one dimension of 100 nanometers or less. Such materials typically possess nanostructure-dependent properties (e.g., chemical, mechanical, electrical, optical, magnetic, biological), which make them desiderable for commercial or medical application. However, these same properties may potentially lead to nanostructure-dependent biological activity that differs from and is not directly predicted by the bulk properties of the constitutive chemicals and compounds. Nanoparticles and nanomaterials can be on the same scale of living cells components, including proteins, nucleic acids, lipids and cellular organelles. When considering nanoparticles it must be asked how man-made nanostructures can interact with or influence biological systems. Carbon nanotubes (CNTs) are an example of carbon-based nanomaterial, which has won a huge spreading in nanotechnology. The incorporation of CNTs in living systems has raised many concerns because of their hydrophobicity and tendency to aggregate and accumulate into cells, organs, and tissues with dangerous effects.

Applications of toxicogenomics to both investigative and predictive toxicology will contribute to the in-depth investigation of molecular mechanisms or the mode of nanomaterials action that is achieved by using conventional toxicological approaches. Parallel toxicogenomic technologies will promote a valuable platform for the development of biomarkers, in order to predict possible nanomaterial’s toxicity. The potential of characteristic gene expression profiles (“fingerprint”) of exposure or toxicological response to nanoparticles will be discussed in the review to enhance comprehension of the molecular mechanism of in vivo and in vitro system exposed to nanomaterials.