Current Opinion in Genetics & Development

Published by Elsevier
Print ISSN: 0959-437X
Somatic cell gene therapy for the correction of many human genetic diseases is now technically possible. We review several methods of gene transfer that have been successfully used in animal studies, and discuss the promise and potential limitations of these methods in the treatment of human genetic diseases.
The study of organ size control is a discipline of developmental biology that is largely unexplored. Although the size of an organ or organism depends largely on cell numbers and cell size, studies have found that the simple deregulation of cell proliferation or cell growth does not necessarily lead to changes in organ size. Recent genetic screens in Drosophila suggest that mutations that do affect organ size can be classified into three broad categories on the basis of their underlying effects: patterning, proliferation, and growth. Overall, experimental data suggest that organ size might be regulated by a 'total mass checkpoint' mechanism which functions to link the regulation of cell size and cell proliferation. The mechanisms of organ size control could also be critical targets for evolutionary events or disease processes such as tumorigenesis.
The ability of intracellular signaling networks to orchestrate a complex biological response such as cell motility requires that individual signaling proteins must act as integrators, responding to multiple extracellular inputs and regulating multiple signaling pathway outputs. In this review, we highlight recent findings that place focal adhesion kinase (FAK) in an important receptor-proximal position in the regulation of growth factor and integrin-stimulated cell motility. Emphasis is placed on the molecular mechanisms of FAK activation, connections of FAK to focal contact formation as well as turnover, and the potential that FAK function in promoting cell invasion may be distinct from its role in cell motility.
Members of a family of Ets domain proteins, the ternary complex factors (TCFs), are recruited to the c-fos serum response element by interaction with the serum response factor. Recent findings indicate that phosphorylation of TCFs occurs in response to activation of the MAP kinase pathway, and that regulation of TCF activity is an important mechanism by which the serum response element responds to growth factor signals.
Tumor blood vessels have multiple structural and functional abnormalities. They are unusually dynamic, and naturally undergo sprouting, proliferation, remodeling or regression. The vessels are irregularly shaped, tortuous, and lack the normal hierarchical arrangement of arterioles, capillaries and venules. Endothelial cells in tumors have abnormalities in gene expression, require growth factors for survival and have defective barrier function to plasma proteins. Pericytes on tumor vessels are also abnormal. Aberrant endothelial cells and pericytes generate defective basement membrane. Angiogenesis inhibitors can stop the growth of tumor vessels, prune existing vessels and normalize surviving vessels. Loss of endothelial cells is not necessarily accompanied by simultaneous loss of pericytes and surrounding basement membrane, which together can then provide a scaffold for regrowth of tumor vessels. Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets.
Expression of RAS proteins can have either positive or negative effects on cell growth, differentiation and death. New technologies are being developed for the generation of animal models to address the questions of where, when and how much Ras is expressed during tumorigenesis, and how these disparate signals are integrated during multistage carcinogenesis.
Recent years have seen unprecedented characterization of mammalian chromatin thanks to advances in chromatin assays, antibody development, and genomics. Genome-wide maps of chromatin state can now be readily acquired using microarrays or next-generation sequencing technologies. These datasets reveal local and long-range chromatin patterns that offer insight into the locations and functions of underlying regulatory elements and genes. These patterns are dynamic across developmental stages and lineages. Global studies of chromatin in embryonic stem cells have led to intriguing hypotheses regarding Polycomb/trithorax and RNA polymerase roles in 'poising' transcription. Chromatin state maps thus provide a rich resource for understanding chromatin at a 'systems level', and a starting point for mechanistic studies aimed at defining epigenetic controls that underlie development.
The MCM2-7 complex is essential for both the initiation and elongation phases of eukaryotic chromosome replication. There is some evidence that MCM2-7 proteins may act as a DNA helicase; at the same time, a variety of other DNA helicases have also been implicated in the replication of eukaryotic chromosomes.
The combination of complete genome sequence information and estimates of mRNA abundances have begun to reveal causes of both silent and protein sequence evolution. Translational selection appears to explain patterns of synonymous codon usage in many prokaryotes as well as a number of eukaryotic model organisms (with the notable exception of vertebrates). Relationships between gene length and codon usage bias, however, remain unexplained. Intriguing correlations between expression patterns and protein divergence suggest some general mechanisms underlying protein evolution.
Although the stroma within carcinogenic lesions is known to be supportive and responsive to tumors, new data increasingly show that the stroma also has a more active, oncogenic role in tumorigenesis. Stromal cells and their products can transform adjacent tissues in the absence of pre-existing tumor cells by inciting phenotypic and genomic changes in the epithelial cells. The oncogenic action of distinctive stromal components has been demonstrated through a variety of approaches, which provide clues about the cellular pathways involved.
Recently, key advances in biochemical and structural studies of RNA polymerase II (pol II) and the basal transcriptional machinery have shed considerable light on the basic mechanisms underlying the initiation stage of eukaryotic mRNA synthesis. The development of methods for obtaining crystal structures of pol II and its complexes has revolutionized transcriptional studies and holds promise that aspects of initiation will soon be understood at atomic resolution; crosslinking studies have revealed intriguing features of the topology of the pol II initiation complex and provided working models for dynamic steps of initiation; and mechanistic studies have identified promoter escape as a critical step during initiation and brought to light novel roles for the general initiation factors TFIIE, TFIIF, and TFIIH in this process.
Precancerous and malignant cells can induce an immune response which results in the destruction of transformed and/or malignant cells, a process known as immune surveillance. However, immune surveillance is not always successful, resulting in 'edited' tumors that have escaped immune surveillance. Immunoediting is not simply because of the absence of antitumor immunity, but is because of protumor immunity that blocks antitumor adaptive and innate responses, and promotes conditions that favor tumor progression. Several immune protumor effector mechanisms are upregulated by chronic inflammation, leading to the hypothesis that inflammation promotes carcinogenesis and tumor growth by altering the balance between protumor and antitumor immunity, thereby preventing the immune system from rejecting malignant cells, and providing a tumor-friendly environment for progressive disease.
Centromeres provide a distinctive mechanical function for the chromosomes as the site of kinetochore assembly and force generation in mitosis and meiosis. Recent studies show that a unique form of chromatin, based on the histone-H3-like protein CENP-A and homologues, provides a conserved foundation for this mechanical chromatin domain. CENP-A plays a role in templating kinetochore assembly and may be a central element in the epigenetic maintenance of centromere identity. Cohesion at the centromere, intimately linked to kinetochore assembly, is required for integrating spindle forces exerted across the centromere and for establishing the bipolar geometry of sister kinetochores.
Histone acetyltransferases (HATs) directly link chromatin modification to gene activation. Recent structure/function studies provide insights into HAT catalysis and histone binding, and genetic studies suggest cross-talk between acetylation and other histone modifications. Developmental aberrations in mice and certain human cancers are associated with HAT mutations, further highlighting the importance of these enzymes to normal cell growth and differentiation.
Recent studies highlight characteristics of epidermal stem cells that were not fully appreciated before. Stem cells are multipotential and signals exchanged with their neighbours help to regulate exit from the stem cell compartment and differentiation along specific lineages. Stem cells exhibit a high degree of spatial organisation, and cell clustering and motility contribute to the assembly and maintenance of the epidermis.
The past year has seen major advances in our understanding of chromosome structure, driven by technology that allows the rapid construction of physical and genetic maps. Information on the structure and organization of human chromosome 11 is rapidly being accumulated as a result of these developments.
Autophagy is the mechanism by which cells consume parts of themselves to survive starvation and stress. This self-cannibalization limits cell death and tissue inflammation, recycles energy and biosynthetic substrates and removes damaged proteins and organelles, accumulation of which is toxic. In normal tissues, autophagy-mediated damage mitigation may suppress tumorigenesis, while in advanced tumors macromolecular recycling may support survival by buffering metabolic demand under stress. As a result, autophagy-activation in normal cells may suppress tumorigenesis, while autophagy inhibition may be beneficial for the therapy of established tumors. The mechanisms by which autophagy supports cancer cell metabolism are slowly emerging. As cancer is being increasingly recognized as a metabolic disease, how autophagy-mediated catabolism impacts cellular and mammalian metabolism and tumor growth is of great interest. Most cancer therapeutics induce autophagy, either directly by modulating signaling pathways that control autophagy in the case of many targeted therapies, or indirectly in the case of cytotoxic therapy. However, the functional consequence of autophagy induction in the context of cancer therapy is not yet clear. A better understanding of how autophagy modulates cell metabolism under various cellular stresses and the consequences of this on tumorigenesis will help develop better therapeutic strategies against cancer prevention and treatment.
Extracellular metal-dependent proteinases regulate cell behavior by remodeling stromal and cell surface proteins, thereby influencing cell recruitment, cell shape, motility, proliferation, survival, genomic (in)stability, and differentiation. In recent years, the importance of proteinase-induced signaling has been underscored by evidence that altered regulation of cell-extracellular matrix and cell-cell interactions by proteinases can contribute, in a causal manner, to neoplastic progression.
For more than a century, developments in light microscopy drove forward our understanding of how chromosomes are organized in the cell nucleus. Now, derivatives of the chromosome conformation capture (3C) technique have harnessed the power of molecular biology to provide more genome-wide perspectives on the spatial relationships of DNA sequences, both within and between chromosomes. Here we consider what new insights into chromosome territory organization and mechanisms of gene regulation these innovative tools are providing, and the extent to which the visual and the molecular approaches give consistent or differing views of chromosome territory organization.
Genetic studies have identified residues in the structured regions of the histones that are critically involved in the formation of heterochromatin. Any investigation of the events that regulate access to the chromatin substrate must take into account the dynamic nature of the nucleosome, and the regulated inter-conversion between various levels of chromatin higher-order structure.
The two products of the Ink4a-Arf locus, p16(Ink4a) and p19(Arf) (p14(ARF) in humans), are potent tumor suppressors that regulate the activities of the retinoblastoma protein and the p53 transcription factor. These proteins form part of a signaling network that is disrupted in most, if not all, cancer cells. The Ink4a-Arf locus responds to stress signals, limiting cell proliferation and modulating oncogene-induced apoptosis. Recent evidence emerging from mouse tumor models distinguishes the activities of p16(Ink4a) and p19(Arf) in regulating tumor onset and identifies differences in their responsiveness to drugs.
Members of the Swi/Snf family of chromatin-remodeling complexes play critical roles in transcriptional control. Recent studies have made significant advances in our understanding of the fundamental aspects of Swi/Snf complexes, including the roles of specific subunits, the repression of transcription, and the mechanism of remodeling. In addition, new findings also indicate an important role for the Swi/Snf-related complex, RSC, in controlling gene expression.
The adult mammalian brain harbors multipotent stem cells, which reside and participate in specialized niches that support self-renewal and differentiation. The first cellular and molecular elements of the stem cell niche in the adult brain have been identified and include cell-cell interactions and somatic cell signaling, the vasculature, the extracellular matrix and basal lamina. Furthermore, regulation at the epigenetic level via chromatin modification and remodeling is an integral aspect of stem cell biology. Understanding the in vivo stem cell niche will provide a framework for the elucidation of stem cell function in the adult brain.
Polycomb group (PcG) proteins play important roles in maintaining the repressed transcriptional state of genes. PcG proteins operate as part of Polycomb repressive complexes (PRCs). 'Core' PRCs have been purified that contain only a limited number of PcG proteins. In addition, many gene regulatory proteins have been identified to interact with PcG proteins. However, it remains subject to discussion whether these interactions are transient or whether the regulatory proteins are real components of PRCs. It has also become clear that the compositions of 'core' PRCs differ amongst cell types and that extensive changes in compositions occur during the embryonic development of cells. Because of these dynamic changes, we argue that speaking of a definitive core PRC can be misleading.
The von Hippel-Lindau tumor suppressor protein (pVHL) is the substrate-recognition module of an E3 ubiquitin ligase that targets the alpha subunits of hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. Recognition of HIF by pVHL is linked to enzymatic hydroxylation of conserved prolyl residues in the HIF alpha subunits by members of the EGLN family. Dysregulation of HIF-target genes such as vascular endothelial growth factor and transforming growth factor alpha has been implicated in the pathogenesis of renal cell carcinomas and of hemangioblastomas, both of which frequently lack pVHL function.
Dosage compensation mechanisms in flies and mammals provide an exquisite example of chromatin associated RNAs in chromosome-wide transcription regulation. Recent progress shows that chromatin modifications are also closely linked to these processes. Concerted action of the RNA/chromatin-modifying enzymes may play a crucial role in determining transcriptional output. Furthermore, non-coding RNAs appear to play a dual role, being targeting modules as well as encoding for target sites for complex recognition.
A great challenge in understanding biological complexity in the post-genome era is to reconstruct the regulatory networks governing the patterns of gene expression. In the past few years, the rapid accumulation of genomic sequence and functional data has led to the development of computational approaches to systematically dissect transcriptional regulatory networks. Effective algorithms have been developed to predict cis-regulatory elements in a genome, to identify the target genes of transcription factors, to infer the conditions under which each transcription factor is either activated or deactivated, and to analyze combinatorial regulation by multiple transcription factors. Genomic approaches have profoundly changed the way biologists investigate transcriptional regulation, and global pictures of the transcription networks for several model organisms are beginning to emerge.
The regulation of transcription elongation within the context of chromatin is a topic of great interest. Even though chromatin presents a barrier to transcription by the PolII machinery in vitro, this process is rather efficient in vivo. Importantly, the chromatin structure of the actively transcribed genes is altered as part of this process. A large number of factors implicated in the control of transcript elongation have been identified through genetics, biochemistry and targeted proteomics approaches. However the precise roles and mechanisms of action of these factors remain obscure. A significant advance came about this past year with the elucidation of the roles of FACT and Spt6 in transcription elongation. These factors facilitate PolII passage through chromatin by destabilizing the nucleosome structure as well as reassemble nucleosomes traversed by PolII.
Epigenetic marks, such as cytosine methylation and post-translational histone modifications, are important for interpreting and managing eukaryotic genomes. Recent genetic studies in plants have uncovered details on the different interwoven mechanisms that are responsible for specification of genomic cytosine methylation patterns. These mechanisms include targeting cytosine methylation using heterochromatic histone modifications and RNA guides. Genomic cytosine methylation patterns also reflect locus-specific demethylation initiated by specialized DNA glycosylases. While genetics continues to more fully define these mechanisms, genomic studies in Arabidopsis have yielded an unprecedented high-resolution view of how epigenetic marks are layered over a genome.
The establishment of left-right asymmetries in the vertebrate embryo is carried out by complex genetic interactions that impart left- or right-sided information to the developing organs and structures. The origin of LR information is still unclear, but recent advances have provided new insights as to how it is relayed to the embryo node, and thereafter to the lateral plate mesoderm. In both steps, signaling by members of the transforming growth factor-beta superfamily plays critical roles in amplifying and spreading LR cues, which are reviewed here.
The three phases of liver development that are the focus of this review are: the specification of hepatoblasts within the endoderm, the lineage split of hepatoblasts into hepatocytes and biliary cells, and the interaction of these cells with different mesodermal cell derivatives during liver morphogenesis. Advances in these areas include new genes and experimental models for studying liver development, the role of HNF6 and HNF1beta transcription factors and notch signaling in the hepatocyte-biliary cell lineage decision, the identification of genomic targets for HNF4, and HNF4's role in controlling hepatic epithelial structure and the sinusoidal organization of the liver.
Differentiation of smooth muscle cells (SMCs) is accompanied by the transcriptional activation of an array of muscle-specific genes that confer the unique contractile and physiologic properties of this muscle cell type. The majority of smooth muscle genes are controlled by serum response factor (SRF), a widely expressed transcription factor that also regulates genes involved in cell proliferation. Myocardin and myocardin-related transcription factors (MRTFs) interact with SRF and potently stimulate SRF-dependent transcription. Gain- and loss-of-function experiments have shown myocardin to be sufficient and necessary for SMC differentiation. SMCs are highly plastic and can switch between differentiated and proliferative states in response to extracellular cues. Suppression of SMC differentiation by growth factor signaling is mediated, at least in part, by the displacement of myocardin from SRF by growth factor-dependent ternary complex factors. The association of SRF with myocardin and MRTFs provides a molecular basis for the activation of SMC genes by SRF and the responsiveness of the smooth muscle differentiation program to growth factor signaling.
ATP-dependent chromatin remodelling enzymes act to alter chromatin structure during gene regulation. Studies of the ATPase motors that drive these enzymes support the notion that they function as ATP-dependent DNA translocases with limited processivity. The action of these enzymes on nucleosomes results in the alteration of nucleosome positioning and structure. Recent studies have shown that ATP-dependent chromatin remodelling can also either remove or exchange histone dimers between nucleosomes. This provides a new means by which the incorporation of histone variants can be directed. Additional observations support roles for ATP-dependent remodelling enzymes throughout the transcription cycle.
Recent experiments reveal the role of transcription factors in integrating upstream signals to execute specification and differentiation of epidermal cells. Based on the skin phenotype observed with misregulation of transcription factors such as p63, c-Myc, RelA, pRb, Klf4 and others, their function in controlling proliferation and differentiation is dissected. Understanding the pathways regulated by these factors and their coordinate interactions remains a challenge for the future.
Polycomb group (PcG) proteins are important for maintaining the silenced state of homeotic genes. Biochemical and genetic studies in Drosophila and mammalian cells indicate that PcG proteins function in at least two distinct protein complexes: the ESC-E(Z) or EED-EZH2 complex, and the PRC1 complex. Recent work has shown that at least part of the silencing function of the ESC-E(Z) complex is mediated by its intrinsic activity for methylating histone H3 on lysine 27. In addition to being involved in Hox gene silencing, the complex and its associated histone methyltransferase activity are important in other biological processes including X-inactivation, germline development, stem cell pluripotency and cancer metastasis.
Aurora kinases play critical roles in chromosome segregation and cell division. They are implicated in the centrosome cycle, spindle assembly, chromosome condensation, microtubule-kinetochore attachment, the spindle checkpoint and cytokinesis. Aurora kinases are regulated through phosphorylation, the binding of specific partners and ubiquitin-dependent proteolysis. Several Aurora substrates have been identified and their roles are being elucidated. The deregulation of Aurora kinases impairs spindle assembly, checkpoint function and cell division, causing missegregation of individual chromosomes or polyploidization accompanied by centrosome amplification. Aurora kinases are frequently overexpressed in cancers and the identification of Aurora A as a cancer-susceptibility gene provides a strong link between mitotic errors and carcinogenesis.
Imprinted genes play important roles in development, and most are clustered in large domains. Their allelic repression is regulated by 'imprinting control regions' (ICRs), which are methylated on one of the two parental alleles. Non-histone proteins and nearby sequence elements influence the establishment of this differential methylation during gametogenesis. DNA methylation, histone modifications, and also polycomb group proteins are important for the somatic maintenance of imprinting. The way ICRs regulate imprinting differs between domains. At some, the ICR constitutes an insulator that prevents promoter-enhancer interactions, when unmethylated. At other domains, non-coding RNAs could be involved, possibly by attracting chromatin-modifying complexes. The latter silencing mechanism has similarities with X-chromosome inactivation.
New structural studies of RNA polymerase II (Pol II) complexes mark the beginning of a detailed mechanistic analysis of the eukaryotic mRNA transcription cycle. Crystallographic models of the complete Pol II, together with new biochemical and electron microscopic data, give insights into transcription initiation. The first X-ray analysis of a Pol II complex with a transcription factor, the elongation factor TFIIS, supports the idea that the polymerase has a 'tunable' active site that switches between mRNA synthesis and cleavage. The new studies also show that domains of transcription factors can enter polymerase openings, to modulate function during transcription.
Many genomic sequences have been recently published for bacteria that can replicate only within eukaryotic hosts. Comparisons of genomic features with those of closely related bacteria retaining free-living stages indicate that rapid evolutionary change often occurs immediately after host restriction. Typical changes include a large increase in the frequency of mobile elements in the genome, chromosomal rearrangements mediated by recombination among these elements, pseudogene formation, and deletions of varying size. In anciently host-restricted lineages, the frequency of insertion sequence elements decreases as genomes become extremely small and strictly clonal. These changes represent a general syndrome of genome evolution, which is observed repeatedly in host-restricted lineages from numerous phylogenetic groups. Considerable variation also exists, however, in part reflecting unstudied aspects of the population structure and ecology of host-restricted bacterial lineages.
Tissue development, homeostasis and tumor pathogenesis all depend upon a complex dialogue between multiple cell types operating within a dynamic three-dimensional (3D) tissue extracellular matrix microenvironment. A major issue is whether the spatial organization of a cell within this 3D tissue microenvironment could modulate cell responsiveness to regulate cell fate decisions such as survival, and if so how. Classic developmental model systems and transgenic animals are instructive but pose special challenges for investigators conducting signaling studies and biochemical assays in tissues. As an alternative, 3D culture model systems exist in which cell-adhesion dependent tissue architecture, heterotypic cell-cell interactions and tissue differentiation can be recapitulated with good fidelity. 3D cell culture models are slowly revealing how tissue architecture can dramatically influence how a cell responds to exogenous stimuli to modify its apoptotic behavior and hence should prove instrumental for identifying novel cell death pathways.
Our increased knowledge of epigenetic reprogramming supports the idea that epigenetic marks are not always completely cleared between generations. Incomplete erasure at genes associated with a measurable phenotype can result in unusual patterns of inheritance from one generation to the next. It is also becoming clear that the establishment of epigenetic marks during development can be influenced by environmental factors. In combination, these two processes could provide a mechanism for a rapid form of adaptive evolution.
The pluripotent state of embryonic stem cells is maintained by a core network of transcription factors, and by chromatin remodelling factors that support an environment permissive for transcription. Polycomb and trithorax Group proteins enable 'bivalent' chromatin to be established at lineage-specific genes within pluripotent cells that is thought to poise genes for rapid activation upon induction of differentiation. As differentiation proceeds, chromatin condenses and there is a genome-wide increase in the abundance of repressive histone modifications, alterations in the subnuclear organisation of particular genomic regions, and changes in DNA methylation profiles within genes. Reprogramming of somatic cells provides a platform to investigate the role of chromatin-based factors in establishing and maintaining pluripotency.
The nuclear hormone receptors constitute a large family of transcription factors. The binding of the hormonal ligands induces nuclear receptors to assume a configuration that leads to transcriptional activation. Recent studies of retinoic acid and thyroid hormone receptors revealed that, upon ligand binding, a histone deacetylase (HDAC)-containing complex is displaced from the nuclear receptor in exchange for a histone acetyltransferase (HAT)-containing complex. These observations suggest that ligand-dependent recruitment of chromatin-remodeling activity serves as a general mechanism underlying the switch of nuclear receptors from being transcriptionally repressive to being transcriptionally active.
The name heterochromatin protein 1 (HP1) suggests that this small nuclear factor plays a role in forming heterochromatic domains. It was noticed years ago, however, that the distribution of HP1 on polytene chromosomes was not restricted to chromocenters or telomeres. HP1 was also found, reproducibly, along the euchromatic arms. A possible function in euchromatic gene regulation was postulated. Now, a large body of data has blurred the definition of HP1 as a structural component of heterochromatin, revealing its two-faced nature. Not only do HP1 isoforms have specific binding sites in both heterochromatic and euchromatic domains but they might also participate in the repression and activation of transcription in both compartments.
Polycomb group (PcG) proteins are transcriptional repressors that control expression of developmental regulator genes in animals and plants. Recent advances in our understanding of the PcG system include biochemical purifications that revealed a substantial variety in PcG complex composition. These different complexes contain distinct chromatin-modifying activities and engage in cross-talk with other chromatin modifications. Complementing these biochemical analyses, structural studies have begun to provide insight into how PcG proteins interact with each other and with chromatin. Finally, genome-wide binding profiling and the ensuing functional analysis of target gene regulation revealed that the PcG system is not only used for the permanent silencing of developmental regulator genes. Rather, PcG mediated repression also constitutes a mechanism for dynamic control of gene transcription.
Nucleosome-remodelling factors are key facilitators of chromatin dynamics. At the level of single nucleosomes, they are involved in nucleosome-repositioning, altering histone-DNA interactions, disassembly of nucleosomes, and the exchange of histones with variants of different properties. The fundamental nature of chromatin dictates that nucleosome-remodelling affects all aspects of eukaryotic DNA metabolism, but much less is known about the functional interactions of nucleosome-remodelling factors with folded chromatin fibres. Because remodelling machines are abundant constituents of eukaryotic nuclei and, therefore, have ample potential to interact with chromatin, they might also affect higher-order chromatin architecture. Recent observations support roles for nucleosome-remodelling factors at the supra-nucleosomal level.
Paramutation involves trans-interactions between alleles or homologous sequences that establish distinct gene expression states that are heritable for generations. It was first described in maize by Alexander Brink in the 1950s, with his studies of the red1 (r1) locus. Since that time, paramutation-like phenomena have been reported in other maize genes, other plants, fungi, and animals. Paramutation can occur between endogenous genes, two transgenes or an endogenous gene, and transgene. Recent results indicate that paramutation involves RNA-mediated heritable chromatin changes and a number of genes implicated in RNAi pathways. However, not all aspects of paramutation can be explained by known mechanisms of RNAi-mediated transcriptional silencing.
Drosophila is a model system for cancer research. Investigation with fruit flies has facilitated a number of important recent discoveries in the field: the hippo signaling pathway, which coordinates cell proliferation and death to achieve normal tissue size; 'social' behaviors of cells, including cell competition and apoptosis-induced compensatory proliferation, that help ensure normal tissue size; and a growing understanding of how oncogenes and tumor suppressors cooperate to achieve tumor growth and metastasis in situ. In the future, Drosophila models can be extended beyond basic research in the search for human therapeutics.
A long-standing debate in developmental biology concerns the extent to which embryos are largely 'mosaic' (cell fates are allocated by localization of maternal determinants that are inherited differentially) or 'regulative' (cell interactions determine cell fates). Generally, it has been thought that amniotes, especially birds and mammals, are at the extreme regulative end of the spectrum, whereas most invertebrates, lower chordates and anamnia are more mosaic. Various studies have identified additional differences, including egg size, the timing of zygotic transcription and the speed of development. However, new research is starting to reveal among the vertebrate classes an astonishing degree of conservation in the intercellular signalling mechanisms that regulate cell fate and embryonic polarity before gastrulation.
Recent successes using Gleevec for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors have provided proof that strategies to target signal transduction pathways mutated in human cancers can work. However, the application of this strategy to other cancers has been slow. Central to alleviating this impedance is the molecular characterization of the tumors. There is an urgent need to translate basic scientific findings into relevant, clinically applicable molecular diagnostic assays.
Top-cited authors
Adrian Bird
  • The University of Edinburgh
Arian Smit
  • Institute for Systems Biology
Shelley Berger
  • University of Pennsylvania
Charles J. Sherr
  • St. Jude Children's Research Hospital
Richard Kolodner
  • Ludwig Institute for Cancer Research, UC San Diego School of Medicine