Latest Articles Include:
- Editorial Board
- Trends Genet 27(12):i (2011)
- Nucleosomes and the accessibility problem
- Trends Genet 27(12):487-492 (2011)
Eukaryotic DNA is packaged in nucleosomes. How does this sequestration affect the ability of transcription regulators to access their sites? We cite evidence against the idea that nucleosome positioning is determined primarily by the intrinsic propensities of DNA sequences to form nucleosomes – such that, for example, regulatory sites would be 'nucleosome-free'. Instead, studies in yeast show that nucleosome positioning is primarily determined by specific DNA-binding proteins. Where nucleosomes would otherwise compete with regulatory protein binding (a modest but potentially biologically important effect), this obstacle can be relieved by at least two strategies for exposing regulatory sites. In contrast to their lack of effect on nucleosome positioning, DNA sequence differences do directly affect both the efficiencies with which nucleosomes form in regions flanking regulatory sites before induction, and the extent of their removal upon induction. These nucleosom! es, evidently, inhibit basal transcription but are poised to be removed quickly upon command.
- Genome-wide association studies and systems biology: together at last
- Trends Genet 27(12):493-498 (2011)
Following the widespread use of genome-wide association studies to elucidate the genetic architectures of complex phenotypes, there has been a push to augment existing observational studies with additional layers of molecular information. The resulting high-dimensional data have led the emergence of research in integrative systems biology. Here, we examine recent progress in characterizing biological networks as well as the corresponding conceptual and analytical challenges. Using examples from metabolomics, we contend that integrative systems biology should prompt a re-examination of conventional phenotypic measures where heterogeneous or correlated phenotypes can be fine-mapped. Although still in its infancy, it is apparent that the large-scale characterization of molecular systems will transform our understanding of phenotype, biology and pathogenesis.
- Sticking a fork in cohesin â" it's not done yet!
- Trends Genet 27(12):499-506 (2011)
To identify the products of chromosome replication (termed sister chromatids) from S-phase through M-phase of the cell cycle, each sister pair becomes tethered together by specialized protein complexes termed cohesins. To participate in sister tethering reactions, chromatin-bound cohesins become modified by establishment factors that function during S-phase and bind to DNA replication-fork components. Early models posited that establishment factors might move with replication forks, but that fork progression takes place independently of cohesion pathways. Recent studies now suggest that progression of the replication fork and/or S-phase are slowed in cohesion-deficient cells. These findings have led to speculations that cohesin ring-like structures normally hinder fork progression but coordinate origin firing during replication. Neither model, however, fully explains the diverse effects of cohesion mutation on replication kinetics. I discuss these challenges and then o! ffer alternative views that include cohesin-independent mechanisms for replication-fork destabilization and transcription-based effects on S-phase progression.
- Xenopus research: metamorphosed by genetics and genomics
- Trends Genet 27(12):507-515 (2011)
Research using Xenopus takes advantage of large, abundant eggs and readily manipulated embryos in addition to conserved cellular, developmental and genomic organization with mammals. Research on Xenopus has defined key principles of gene regulation and signal transduction, embryonic induction, morphogenesis and patterning as well as cell cycle regulation. Genomic and genetic advances in this system, including the development of Xenopus tropicalis as a genetically tractable complement to the widely used Xenopus laevis, capitalize on the classical strengths and wealth of achievements. These attributes provide the tools to tackle the complex biological problems of the new century, including cellular reprogramming, organogenesis, regeneration, gene regulatory networks and protein interactions controlling growth and development, all of which provide insights into a multitude of human diseases and their potential treatments.
- Epigenetic factors influencing resistance to nuclear reprogramming
- Trends Genet 27(12):516-525 (2011)
Patient-specific somatic cell reprogramming is likely to have a large impact on medicine by providing a source of cells for disease modelling and regenerative medicine. Several strategies can be used to reprogram cells, yet they are generally characterised by a low reprogramming efficiency, reflecting the remarkable stability of the differentiated state. Transcription factors, chromatin modifications, and noncoding RNAs can increase the efficiency of reprogramming. However, the success of nuclear reprogramming is limited by epigenetic mechanisms that stabilise the state of gene expression in somatic cells and thereby resist efficient reprogramming. We review here the factors that influence reprogramming efficiency, especially those that restrict the natural reprogramming mechanisms of eggs and oocytes. We see this as a step towards understanding the mechanisms by which nuclear reprogramming takes place.