Current Genomics

ISSN: 1389-2029

Current Genomics
Volume 9, Number 5, August 2008

Contents


Recent Advances in the Characterization of Genetic Factors Involved in Human Susceptibility to Infection by Schistosomiasis Pp. 290-300
A. Isnard and C. Chevillard
[Abstract]


Post-Translational Control of Sp-Family Transcription Factors Pp. 301-311
J.S. Waby, C.D. Bingle and B.M. Corfe
[Abstract]


How Drosophila melanogaster Forms its Mechanoreceptors Pp. 312-323
D.P. Furman and T.A. Bukharina
[Abstract]


Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms Pp. 324-337
P. Gao, Y. Jiao, Q. Xiong, C.-Y. Wang, I. Gerling and W. Gu
[Abstract]


Multiple Hsp70 Isoforms in the Eukaryotic Cytosol: Mere Redundancy or Functional Specificity? Pp. 338-348
M. Kabani and C.N. Martineau
[Abstract]


Can Systems Biology Understand Pathway Activation? Gene Expression Signatures as Surrogate Markers for Understanding the Complexity of Pathway Activation Pp. 349-360
H. Itadani, S. Mizuarai and H. Kotani
[Abstract]




Abstracts


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Recent Advances in the Characterization of Genetic Factors Involved in Human Susceptibility to Infection by Schistosomiasis
A. Isnard and C. Chevillard

Human resistance to infection by schistosomes is associated to a strong Th2 immune. However a persistent Th2 response can cause severe kidney and liver disease in human. In this review, we mainly focused on the control of infection levels caused by schistosomes. Several experimental models allowed us to better understand the immunological mechanisms of the host against schistosome infection. High IgE and eosinophil levels are associated with resistance to infection by schistosomes and this effect is counterbalanced by IgG4. IgE and eosinophils are highly dependent on IL-4, IL-13, and Il-5, which are three main Th2 cytokines. We also examined the genetic factors involved in human susceptibility to infection by schistosomiasis. Infection levels are mainly regulated by a major locus SM1, in 5q31-q33 region, which contains the genes encoding for the IL-4, IL-13, and Il-5 cytokines. An association between an IL13 polymorphism, rs1800925, and infection levels has been shown. This polymorphism synergistically acts with another polymorphism (rs324013) in the STAT6 gene, encoding for the signal transducer of the IL13 pathway. This pathway has also been involved in atopic disorders. As helminthiasis, atopy is the result of aberrant Th2 cytokine response to allergens, with an increased production of IL-4, IL-13, Il-9 and Il-5, with high amounts of allergen-specific and total IgE and eosinophilia. However, the Th2 immune response is protective in helminthiasis but aggravating in atopic disorders. Several studies reported interplay between helminthic infections and allergic reactions. The different results are discussed here.


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Post-Translational Control of Sp-Family Transcription Factors
J.S. Waby, C.D. Bingle and B.M. Corfe

Sp-family transcription factors are widely expressed in human tissues and involved in the regulation of many cellular processes and response to cellular microenvironment. These responses appear to be mediated by alterations in transcription factor affinity for DNA rather than altered protein level. How might such changes be effected? This review will identify the range of known post-translational modifications (PTMs) of Sp-factors and the sometimes conflicting literature about the roles of PTMs in regulating activity. We will speculate on the interaction between cell environment, chromatin microenvironment and the role of PTM in governing functionality of the proteins and the complexes to which they belong.


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How Drosophila melanogaster Forms its Mechanoreceptors
D.P. Furman and T.A. Bukharina

A strictly determined number of external sensory organs, macrochaetes, acting as mechanoreceptors, are orderly located on drosophila head and body. Totally, they form the bristle pattern, which is a species-specific characteristic of drosophila.

Each mechanoreceptor comprises four specialized cells derived from the single sensory organ precursor (SOP) cell. The conserved bristle pattern combined with a comparatively simple structure of each mechanosensory organ makes macro-chaetes a convenient model for studying the formation spatial structures with a fixed number of elements at certain posi-tions and the mechanism underlying cell differentiation.

The macrochaete morphogenesis consists of three stages. At the first stage, the proneural clusters segregate from the massive of ectodermal cells of the wing imaginal disc. At the second stage, the SOP cell is determined and its position in the cluster is specified. At the third stage, the SOP cell undergoes two asymmetric divisions, and the daughter cells differentiate into the components of mechanoreceptor: shaft, socket, bipolar neuron, and sheath.

The critical factor determining the neural pathway of cell development is the content of proneural proteins, products of the achaete-scute (AS-C) gene complex, reaching its maximum in the SOP cell.

The experimental data on the main genes and their products involved in the control of bristle pattern formation are systematized. The roles of achaete-scute complex, EGFR and Notch signaling pathways, and selector genes in these processes are considered. An integral scheme describing the functioning of the system controlling macrochaete development in D. melanogaster is proposed based on analysis of literature data.


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Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms
P. Gao, Y. Jiao, Q. Xiong, C.-Y. Wang, I. Gerling and W. Gu

A systematic study has been conducted of all available reports in PubMed and OMIM (Online Mendelian Inheritance in Man) to examine the genetic and molecular basis of quantitative genetic loci (QTL) of diabetes with the main focus on genes and polymorphisms. The major question is, What can the QTL tell us? Specifically, we want to know whether those genome regions differ from other regions in terms of genes relevant to diabetes. Which genes are within those QTL regions, and, among them, which genes have already been linked to diabetes? whether more polymorphisms have been associated with diabetes in the QTL regions than in the non-QTL regions.

Our search revealed a total of 9038 genes from 26 type 1 diabetes QTL, which cover 667,096,006 bp of the mouse genomic sequence. On one hand, a large number of candidate genes are in each of these QTL; on the other hand, we found that some obvious candidate genes of QTL have not yet been investigated. Thus, the comprehensive search of candidate genes for known QTL may provide unexpected benefit for identifying QTL genes for diabetes.


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Multiple Hsp70 Isoforms in the Eukaryotic Cytosol: Mere Redundancy or Functional Specificity?
M. Kabani and C.N. Martineau

Hsp70 molecular chaperones play a variety of functions in every organiism, cell type and organelle, and their activities have been implcated in a number of human pathologies, ranging from cancer to neurodegenerative diseases. The functions, regulations and structure of Hsp70s were intensively studied for about three decades, yet much still remains to be learned about these essential folding enzymes. Genome sequencing efforts revealed that most genomes contain multiple members of the Hsp70 family, some of which co-exist in the same cellular compartment. For example, the human cytosol and nucleus contain six highly homologous Hsp70 proteins while the yeast Saccharomyces cerevisiae contains four canonical Hsp70s and three fungal-specific ribosome-associated and specialized Hsp70s. The reasons and significance of the requirement for multiple Hsp70s is still a subject of debate. It has been postulated for a long time that these Hsp70 isoforms are functionally redundant and differ only by their spatio-temporal expression patterns. However, several studies in yeast and higher eukaryotic organisms challenged this widely accepted idea by demonstrating functional specificity among Hsp70 isoforms. Another element of complexity is brought about by specific cofactors, such as Hsp40s or nucleotide exchange factors that modulate the activity of Hsp70s and their binding to client proteins. Hence, a dynamic network of chaperone/co-chaperone interactions has evolved in each organism to efficiently take advantage of the multiple cellular roles Hsp70s can play. We summarize here our current knowledge of the functions and regulations of these molecular chaperones, and shed light on the known functional specificities among isoforms.


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Can Systems Biology Understand Pathway Activation? Gene Expression Signatures as Surrogate Markers for Understanding the Complexity of Pathway Activation
H. Itadani, S. Mizuarai and H. Kotani

Cancer is thought to be caused by a sequence of multiple genetic and epigenetic alterations which occur in one or more of the genes controlling cell cycle progression and signaling transduction. The complexity of carcinogenic mechanisms leads to heterogeneity in molecular phenotype, pathology, and prognosis of cancers.

Genome-wide mutational analysis of cancer genes in individual tumors is the most direct way to elucidate the complex process of disease progression, although such high-throughput sequencing technologies are not yet fully developed. As a surrogate marker for pathway activation analysis, expression profiling using microarrays has been successfully applied for the classification of tumor types, stages of tumor progression, or in some cases, prediction of clinical outcomes. However, the biological implication of those gene expression signatures is often unclear.

Systems biological approaches leverage the signature genes as a representation of changes in signaling pathways, instead of interpreting the relevance between each gene and phenotype. This approach, which can be achieved by comparing the gene set or the expression profile with those of reference experiments in which a defined pathway is modulated, will improve our understanding of cancer classification, clinical outcome, and carcinogenesis. In this review, we will discuss recent studies on the development of expression signatures to monitor signaling pathway activities and how these signatures can be used to improve the identification of responders to anticancer drugs.