Transcriptional activation: risky business

Transcriptional regulation is all about getting RNA polymerase to the right place on the gene at the right time and making sure that it is competent to conduct transcription. Traditional views of this process place most of their emphasis on the events that precede initiation of transcription. We imagine a promoter-bound transcriptional activator (or collection of activators) recruiting components of the basal transcriptional machinery to the DNA, eventually leading to the recruitment of RNA polymerase II and the onset of gene transcription. Although these events play a crucial role in regulating gene expression, they are only half the story. Correct regulation of transcription requires that polymerase not only initiates when and where it should, but that it stops initiating when no longer appropriate. But how are the signals from transcriptional activators, telling RNA polymerase to fire, terminated! Is this process governed by chance, with activators simply falling off the promoter at a certain frequency? Or is there some more direct mechanism, whereby activators are aggressively limited from uncontrolled promoter activation? A new article by Chi et al. (2001) suggests the latter may be true, and provides a mechanism for how a component of the basal transcription machinery can mark the activators it has encountered, sentencing them to an early death or banishing them from the nucleus. The ability of the basal transcriptional apparatus to mark activators provides an efficient way to limit activator function and ensures that continuing transcription initiation at a promoter is coupled to the continuing synthesis and activation of transcriptional activators

Interaction of the oncoprotein transcription factor MYC with its chromatin cofactor WDR5 is essential for tumor maintenance.

The oncoprotein transcription factor MYC is overexpressed in the majority of cancers. Key to its oncogenic activity is the ability of MYC to regulate gene expression patterns that drive and maintain the malignant state. MYC is also considered a validated anticancer target, but efforts to pharmacologically inhibit MYC have failed. The dependence of MYC on cofactors creates opportunities for therapeutic intervention, but for any cofactor this requires structural understanding of how the cofactor interacts with MYC, knowledge of the role it plays in MYC function, and demonstration that disrupting the cofactor interaction will cause existing cancers to regress. One cofactor for which structural information is available is WDR5, which interacts with MYC to facilitate its recruitment to chromatin. To explore whether disruption of the MYC-WDR5 interaction could potentially become a viable anticancer strategy, we developed a Burkitt\u27s lymphoma system that allows replacement of wild-type MYC for mutants that are defective for WDR5 binding or all known nuclear MYC functions. Using this system, we show that WDR5 recruits MYC to chromatin to control the expression of genes linked to biomass accumulation. We further show that disrupting the MYC-WDR5 interaction within the context of an existing cancer promotes rapid and comprehensive tumor regression in vivo. These observations connect WDR5 to a core tumorigenic function of MYC and establish that, if a therapeutic window can be established, MYC-WDR5 inhibitors could be developed as anticancer agents

Improving estimates of tropical peatland area, carbon storage, and greenhouse gas fluxes

The workshops that led to this article were supported financially by the Universities of Leicester and Nottingham, and the Natural Environment Research Council-funded ‘Earth Observation Technology Cluster’ knowledge exchange initiativeOur limited knowledge of the size of the carbon pool and exchange fluxes in forested lowland tropical peatlands represents a major gap in our understanding of the global carbon cycle. Peat deposits in several regions (e.g. the Congo Basin, much of Amazonia) are only just beginning to be mapped and characterised. Here we consider the extent to which methodological improvements and improved coordination between researchers could help to fill this gap. We review the literature on measurement of the key parameters required to calculate carbon pools and fluxes, including peatland area, peat bulk density, carbon concentration, above-ground carbon stocks, litter inputs to the peat, gaseous carbon exchange, and waterborne carbon fluxes. We identify areas where further research and better coordination are particularly needed in order to reduce the uncertainties in estimates of tropical peatland carbon pools and fluxes, thereby facilitating better-informed management of these exceptionally carbon-rich ecosystems.PostprintPeer reviewe

Sir Henry Hallet Dale

Sir Henry Hallet Dale can undisputedly be accoladed as one of the greatest British pharmacologists of the twentieth century. His work was pivotal in laying down the principles of chemical neurotransmission. This article gives some account of Dale’s life and his most important discoveries, including the identification of acetylcholine as a neurotransmitter in the autonomic and somatic nervous systems

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Rapid Cellular Turnover in Adipose Tissue

It was recently shown that cellular turnover occurs within the human adipocyte population. Through three independent experimental approaches — dilution of an inducible histone 2B-green fluorescent protein (H2BGFP), labeling with the cell cycle marker Ki67 and incorporation of BrdU — we characterized the degree of cellular turnover in murine adipose tissue. We observed rapid turnover of the adipocyte population, finding that 4.8% of preadipocytes are replicating at any time and that between 1–5% of adipocytes are replaced each day. In light of these findings, we suggest that adipose tissue turnover represents a possible new avenue of therapeutic intervention against obesity

Integrative network analysis identified key genes and pathways in the progression of hepatitis C virus induced hepatocellular carcinoma

Background: Incidence of hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) has been increasing in the United States and Europe during recent years. Although HCV-associated HCC shares many pathological characteristics with other types of HCC, its molecular mechanisms of progression remain elusive. Methods: To investigate the underlying pathology, we developed a systematic approach to identify deregulated biological networks in HCC by integrating gene expression profiles with high-throughput protein-protein interaction data. We examined five stages including normal (control) liver, cirrhotic liver, dysplasia, early HCC and advanced HCC. Results: Among the five consecutive pathological stages, we identified four networks including precancerous networks (Normal-Cirrhosis and Cirrhosis-Dysplasia) and cancerous networks (Dysplasia-Early HCC, Early-Advanced HCC). We found little overlap between precancerous and cancerous networks, opposite to a substantial overlap within precancerous or cancerous networks. We further found that the hub proteins interacted with HCV proteins, suggesting direct interventions of these networks by the virus. The functional annotation of each network demonstrates a high degree of consistency with current knowledge in HCC. By assembling these functions into a module map, we could depict the stepwise biological functions that are deregulated in HCV-induced hepatocarcinogenesis. Additionally, these networks enable us to identify important genes and pathways by developmental stage, such as LCK signalling pathways in cirrhosis, MMP genes and TIMP genes in dysplastic liver, and CDC2-mediated cell cycle signalling in early and advanced HCC. CDC2 (alternative symbol CDK1), a cell cycle regulatory gene, is particularly interesting due to its topological position in temporally deregulated networks. Conclusions: Our study uncovers a temporal spectrum of functional deregulation and prioritizes key genes and pathways in the progression of HCV induced HCC. These findings present a wealth of information for further investigation

Macroeconomic policy change: Ireland in comparative perspective

This paper sets out to develop an improved framework for examining critical junctures. This a priori framework is a significant improvement over existing critical juncture frameworks that lack any predictive element. It is an advance for historical institutionalism in particular, and political science in general. After the new framework is set out in detail here, it is tested. The framework is used to examine a number of potential critical junctures in macroeconomic policy, drawn from Ireland, Sweden, Britain, and America in the latter half of the twentieth century

Immunolocalization of Influenza A Virus and Markers of Inflammation in the Human Parkinson's Disease Brain

Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified. Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation. We present immunohistochemical data indicating the presence of influenza A virus within the substantia nigra pars compacta (SNpc) from postmortem PD brain sections. Influenza A virus labeling was identified within neuromelanin granules as well as on tissue macrophages in the SNpc. Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc. The presence of influenza A virus together with macrophages and T-lymphocytes may contribute to the neuroinflammation associated with this disease

Dephosphorylation of Nucleophosmin by PP1β Facilitates pRB Binding and Consequent E2F1-dependent DNA Repair

We report a new pathway through which PP1β signals to nucleophosmin (NPM) in response to DNA damage. UV induces dephosphorylation of NPM at multiple sites, leading to enhancement of complex formation between NPM and retinoblastoma tumor suppressor protein and the subsequent upregulation of E2F1. Consequently, such signaling pathway potentiates the cellular DNA repair capacity