Current Genomics - Volume 11, Issue 4, 2010

Because the basic unit of biology is the cell, biological knowledge is rooted in the epistemology of the cell, and because life is the salient characteristic of the cell, its epistemology must be centered on its livingness, not its constituent components. The organization and regulation of these components in the pursuit of life constitute the fundamental nature of the cell. Thus, regulation sits at the heart of biological knowledge of the cell and the extraordinary complexity of this regulation conditions the kind of knowledge that can be obtained, in particular, the representation and intelligibility of that knowledge. This paper is essentially split into two parts. The first part discusses the inadequacy of everyday intelligibility and intuition in science and the consequent need for scientific theories to be expressed mathematically without appeal to commonsense categories of understanding, such as causality. Having set the backdrop, the second part addresses biological knowledge. It briefly reviews modern scientific epistemology from a general perspective and then turns to the epistemology of the cell. In analogy with a multi-faceted factory, the cell utilizes a highly parallel distributed control system to maintain its organization and regulate its dynamical operation in the face of both internal and external changes. Hence, scientific knowledge is constituted by the mathematics of stochastic dynamical systems, which model the overall relational structure of the cell and how these structures evolve over time, stochasticity being a consequence of the need to ignore a large number of factors while modeling relatively few in an extremely complex environment.

Sonic hedgehog (Shh) signaling is critically important for embryogenesis and other cellular processes in which GLI transcription factors mediate the terminal effects of the pathway. GLI1, in particular, plays a significant role in human cancers. Consequently, GLI1 and its upstream positive regulator Smoothened (SMO) are important targets of anticancer therapy and several SMO-targeted small molecule inhibitors are being evaluated clinically. Emerging exciting evidence reveals a high level of complexity that lies within the GLI1-mediated pathway. For example, a recent study provided evidence linking the polymorphic GLI1 variants Q1100/E1100 to chronic inflammatory bowel diseases. Two recent reports uncovered the existence of two novel human GLI1 isoforms that differ structurally and functionally from the wildtype GLI1 identified over two decades ago. Interestingly, although both are products of alternative splicing, GLI1ΔN and tGLI1 (truncated GLI1) isoforms are predominantly expressed in normal and malignant tissues, respectively. In addition to these important discoveries, gene expression profiling studies have identified a number of novel wild-type GLI1 and tGLI1 target genes, linking wild-type GLI1 to tumor progression and therapeutic resistance, and tGLI1 to tumor invasion and migration. In light of these new insights, this review will provide a comprehensive overview on GLI1 polymorphisms and the three members of the GLI1 family of proteins, and their impacts on human diseases, including, cancers.

Alzheimer's disease (AD) represents the most common form of dementia in the elderly, characterized by progressive loss of memory and cognitive capacity severe enough to interfere with daily functioning and the quality of life. Rare, fully penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for familial forms of the disease. However, more than 90% of AD is sporadic, likely resulting from complex interactions between genetic and environmental factors. Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased plasma folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired SAM levels in AD brains. Polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with increased Hcy levels in AD individuals. Studies in rodents suggest that early life exposure to neurotoxicants or dietary restriction of folate and other B vitamins result in epigenetic modifications of AD related genes in the animal brains. Similarly, studies performed on human neuronal cell cultures revealed that folate and other B vitamins deprivation from the media resulted in epigenetic modification of the PSEN1 gene. There is also evidence of epigenetic modifications in the DNA extracted from blood and brains of AD subjects. Here I review one-carbon metabolism in AD, with emphasis on possible epigenetic consequences.

Microarray studies have successfully shed light on various aspects of the molecular mechanisms behind the development of hepatocellular carcinoma (HCC), such as the identification of novel molecular subgroups and the genetic profiles associated with metastasis and venous invasion. These experiments, mainly comprising genome wide profiling, potentially represent the basis of novel targeted therapeutic strategies in HCC. In response, we summarize the multiple reported expression profiles in HCC associated with HCC development, novel subgroups, venous invasion and metastasis.

Lack of penetrance and variability of expression are common findings in nonsyndromic hearing loss with autosomal dominant mode of inheritance, but are also seen with recessive inheritance. Now we know that genotype cannot necessarily predict phenotype due to the complexity of the genome, the proteome interacting with the transcriptome, and the dynamically coupled systems that are involved. The contribution of genetic background to phenotypic diversity reflects the additive and interactive (epistasis) effects of multiple genes. Because, individual genes do not act alone but rather in concert with many other genes, it is not surprising that, modifier genes are common source of phenotypic variation in human populations. They can affect the phenotypic outcome of a given genotype by interacting in the same or in a parallel biological pathway as the disease gene. These modifier genes modulate penetrance, dominance, pleiotropy or expressivity in individuals with Mendelian traits and can also be exerted by influencing the severity, the penetrance, the age of onset and the progression of a disease. In this review, we focus on modifier genes that specifically affect hearing loss phenotypes in humans as well as those described in mice. We also include examples of digenic inheritance of deafness, because additive or interactive effects can also result from interaction between two mutant genes.

With the completion and near completion of many malaria parasite genome-sequencing projects, efforts are now being directed to a better understanding of gene functions and to the discovery of vaccine and drug targets. Inter- and intraspecies comparisons of the parasite genomes will provide invaluable insights into parasite evolution, virulence, drug resistance, and immune invasion. Genome-wide searches for loci under various selection pressures may lead to discovery of genes conferring drug resistance or encoding for protective antigens. In addition, the Plasmodium falciparum genome sequence provides the basis for the development of various microarrays to monitor gene expression and to detect nucleotide substitution and deletion/amplification. Genome-wide profiling of the parasite proteome, chromatin modification, and nucleosome position also depend on availability of the parasite genome. In this brief review, we will highlight some recent advances and studies in characterizing gene function and related phenotype in P. falciparum that were made possible by the genome sequence, particularly the development of a genome-wide diversity map and various high-throughput genotyping methods for genome-wide association studies (GWAS).

We have previously found that overexpression of CHF1/Hey2 in the myocardium prevents the development of phenylephrine-induced hypertrophy. To identify transcriptional pathways regulated by CHF1/Hey2, we cultured primary neonatal mouse cardiac myocytes from wild type and transgenic mice overexpressing CHF1/Hey2 and treated them with serum, a potent hypertrophic stimulus. We verified that overexpression of CHF1/Hey2 suppressed cardiac myocyte hypertrophy induced by serum and then determined transcriptional profiles by microarray hybridization. We identified and verified important downstream target genes by single gene analysis and qRT-PCR and then identified important biological processes by Gene Set Analysis using Biological Process Gene Sets from the Gene Ontology Consortium. We found that CHF1/Hey2 suppresses pathways involved in water transport, adenylate cyclase activity, embryonic eye morphogenesis, gut development and fluid transport after serum stimulation. Genes involved in protein dephosphorylation, demonstrate increased expression in myocytes overexpressing CHF1/Hey2, independent of serum treatment. Genes overexpressed prior to serum treatment are involved in regulation of transcription factor activity, nuclear protein export and steroid hormone receptor signaling. Genes overexpressed after serum treatment are involved in autophagy, apoptosis and mitochondrial biogenesis.