Find research datasets worth reusing

Data from: Effectiveness of continence promotion for older women via community organisations: a cluster randomised trial

Objectives: The primary objective of this cluster randomised controlled trial was to compare the effectiveness of the three experimental continence promotion interventions against a control intervention on urinary symptom improvement in older women with untreated incontinence recruited from community organisations. Setting: 71 community organisations across the United Kingdom Participants: 259 women aged 60 years and older with untreated incontinence entered the trial; 88% completed the 3-month follow-up. Interventions: The three active interventions consisted of a single 60-minute group workshop on 1) continence education (20 clusters, 64 women); 2) evidence-based self-management (17 clusters, 70 women); or 3) combined education and self-management (17 clusters, 61 women). The control intervention was a single 60-minute educational group workshop on memory loss, polypharmacy and osteoporosis (17 clusters, 64 women). Primary and secondary outcome measures: The primary outcome was self-reported improvement in incontinence 3 months post-intervention at the level of the individual. The secondary outcome was change in the International Consultation on Incontinence Questionnaire (ICIQ). Changes in incontinence-related knowledge and behaviours were also assessed. Results: The highest rate of urinary symptom improvement occurred in the combined intervention group (66% vs 11% of the control group, prevalence difference 55%, 95% CI 43%-67%, intracluster correlation 0). Thirty percent versus 6% of participants reported significant improvement respectively (prevalence difference 23%, 95% CI 10%-36%, intracluster correlation 0). The number-needed-to-treat was 2 to achieve any improvement in incontinence symptoms, and 5 to attain significant improvement. Compared to controls, the combined group reported an adjusted mean 2.05 point (95% CI 0.87-3.24) greater improvement on the ICIQ. Changes in knowledge and self-reported risk-reduction behaviours paralleled rates of improvement in all intervention arms. Conclusion: Continence education combined with evidence-based self-management improves symptoms of incontinence among untreated older women. Community organisations represent an untapped vector for delivering effective continence promotion interventions.

opencc-zeroDec 2017View details →

Data from: Agri-environmental schemes promote ground-dwelling predators in adjacent oilseed rape fields: diversity, species traits and distance-decay functions

1. Rising demands for agricultural products and high environmental costs of intensive agriculture reinforce the need for ecological replacements in agricultural management. In Europe, agri-environmental schemes (AES) are implemented to enhance species richness and provision of ecosystem services, but the effectiveness of different AES types and the spatial extent of possible beneficial effects are little understood. In this study we assessed the effects of different AES types on diversity, species traits and distance-decay functions of ground- dwelling predators in adjacent crop fields. 2. On 31 study sites with winter oilseed rape (OSR) adjacent to four types of AES differing in management intensity and habitat age we recorded ground-dwelling predators (carabid beetles, staphylinid beetles and spiders) during OSR growth from April to July. Effects of the AES on species richness, activity densities and different traits of these taxa were examined with transects of pitfall traps running along a continuous distance gradient from the AES across the habitat border into the OSR fields. 3. Ground-dwelling predator communities benefitted similarly from the different AES types. In adjacent OSR, activity densities, carabid species richness and the proportion of predatory carabid beetles declined from the field edge while mean body size increased. Adjacent AES increased the proportion of predatory species and simultaneously decreased the proportion of granivorous or frugivorous species in adjacent OSR fields. 4. Synthesis and applications. Our results indicate a beneficial effect of adjacent agri-environmental schemes (AES) on ground-dwelling predators in oilseed rape (OSR), mostly irrespective of AES type and therefore management intensity and habitat age. The short-ranged distance decay effects on natural enemies in OSR underpin that a strategic spatial placement of AES in agricultural landscapes is required to maximise biological pest control. This could help replace anthropogenic input in modern agriculture and secure adequate yields.

opencc-zeroDec 2012View details →

Data from: Delayed virulence and limited costs promote fecundity compensation upon infection

Individuals invest limited resources across vital tasks, like reproduction and survival. Individuals can spread reproductive investment over their life, but cues of death or reduced fitness can influence this investment. In some systems cues of infection induce early but costly reproduction through fecundity compensation as future reproduction becomes uncertain. A key aspect of parasite biology is the delay between exposure to parasites and the onset of virulence. This creates an important window of opportunity for hosts to respond to infection. Existing models have not accounted for this delay or the costs borne by offspring. We combine a theoretical and experimental approach to assess the role of costs and the importance of delay in virulence on fecundity compensation. We find that a delay in virulence selects for plastic fecundity responses even with moderate offspring costs. We tested our model experimentally by exposing pea aphids, Acyrthosiphon pisum, to various ecologically relevant cues of infection and monitored lifetime reproduction and survival of these aphids and their offspring. Our challenges induced fecundity compensation but we did not detect any costs in mothers or offspring. We predict that the relationship between the costs and the delay in onset of virulence, as found here, determines the success of fecundity compensation as an adaptation against parasitism.

opencc-zeroJul 2019View details →

Data from: The bHLH family member ZmPTF1 regulates drought tolerance in maize by promoting root development and ABA synthesis

Drought stress is the most important environmental stress limiting maize production. ZmPTF1, a phosphate starvation-induced basic helix-loop-helix (bHLH) transcription factor (TF), contributes to root development and low-phosphate tolerance in maize. In this paper, ZmPTF1 expression, drought tolerance and the underlying mechanisms were studied by using maize ZmPTF1 overexpression lines and mutants. ZmPTF1 was found to be a positive regulator of root development, ABA synthesis, signalling pathways and drought tolerance. ZmPTF1 was also found to bind to the G-box element within the promoter of 9-cis-epoxycarotenoid dioxygenase (NCED), C-repeat-binding factor (CBF4), ATAF2/NAC081, NAC30 and other TFs and act as a positive regulator of the expression of those genes. The dramatically upregulated NCEDs led to increased ABA synthesis and activation of the ABA signalling pathway. The upregulated TFs hierarchically regulate the expression of the genes involved in root development, stress responses and modifications of transcriptional regulation. The improved root system; increased ABA content; and activated ABA-, CBF4-, ATAF2- and NAC30-mediated stress responses increased the drought tolerance of the ZmPTF1 overexpression lines, while the mutants showed opposite trends. This study describes a useful gene for transgenic breeding and helps us understand the role of a bHLH protein in plant root development and stress responses.

Data from: The Drosophila HNF4 nuclear receptor promotes glucose-stimulated insulin secretion and mitochondrial function in adults

Although mutations in HNF4A were identified as the cause of Maturity Onset Diabetes of the Young 1 (MODY1) two decades ago, the mechanisms by which this nuclear receptor regulates glucose homeostasis remain unclear. Here we report that loss of Drosophila HNF4 recapitulates hallmark symptoms of MODY1, including adult-onset hyperglycemia, glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS). These defects are linked to a role for dHNF4 in promoting mitochondrial function as well as the expression of Hex-C, a homolog of the MODY2 gene Glucokinase. dHNF4 is required in the fat body and insulin-producing cells to maintain glucose homeostasis by supporting a developmental switch toward oxidative phosphorylation and GSIS at the transition to adulthood. These findings establish an animal model for MODY1 and define a developmental reprogramming of metabolism to support the energetic needs of the mature animal.

opencc-zeroNov 2019View details →

Data from: Climate-dependent variation in cold tolerance of weedy rice and rice mediated by OsICE1 promoter methylation

<div class="WordSection1"> The mechanisms by which weedy rice (Oryza sativa f. spontanea) has adapted to endure low-temperature stress in northern latitudes remain unresolved. In this study, we assessed cold tolerance of 100 rice varieties and 100 co-occurring weedy rice populations, which were sampled across a broad range of climates in China. A parallel pattern of latitude-dependent variation in cold tolerance was detected in cultivated rice and weedy rice. At the molecular level, differential cold tolerance was strongly correlated with relative expression levels of CBF cold response pathway genes and with methylation levels in the promoter region of OsICE1, a regulator of this pathway. Among all methylated cytosine sites of the OsICE1 promoter, levels of CHG and CHH methylation were found to be significantly correlated with cold tolerance among accessions. Furthermore, within many of the collection locales, weedy rice shared identical or near-identical OsICE1 methylation patterns with co-occurring cultivated rice. These findings provide new insights on the possible roles that methylation variation in the OsICE1 promoter may play in cold tolerance, and they suggest that weedy rice can rapidly acquire cold tolerance via methylation patterns that are shared with co-occurring rice cultivars. </div>

opencc-zeroDec 2016View details →

Data from: Does high relatedness promote cheater-free multicellularity in synthetic lifecycles?

The evolution of multicellularity is one of the key transitions in evolution and requires extreme levels of cooperation between cells. However, even when cells are genetically identical, non-cooperative cheating mutants can arise that cause a breakdown in cooperation. How then, do multicellular organisms maintain cooperation between cells? A number of mechanisms that increase relatedness amongst cooperative cells have been implicated in the maintenance of cooperative multicellularity including single cell bottlenecks and kin recognition. In this study we explore how relatively simple biological processes such as growth and dispersal can act to increase relatedness and promote multicellular cooperation. Using experimental populations of pseudo-organisms, we found that manipulating growth and dispersal of clones of a social amoeba to create high levels of relatedness was sufficient to prevent the spread of cheating mutants. By contrast cheaters were able to spread under low relatedness conditions. Most surprisingly, we saw the largest increase in cheating mutants under an experimental treatment that should create intermediate levels of relatedness. This is because one of the factors raising relatedness, structured growth, also causes high vulnerability to growth rate cheaters.

opencc-zeroDec 2018View details →

Data from: When resistance is futile, tolerate instead: silicon promotes plant compensatory growth when attacked by above- and belowground herbivores

Plants have evolved numerous herbivore defences which are resistance- or tolerance-based. Resistance involves physical and chemical traits that deter and/or harm herbivores whereas tolerance minimises fitness costs of herbivory, often via compensatory growth. The Poaceae frequently accumulate large amounts of silicon (Si) which can be used for herbivore resistance, including biomechanical and (indirectly) biochemical defences. To date, it is unclear whether Si improves tolerance of herbivory. Here we report how Si enabled a cereal (Triticum aestivum) to tolerate damage inflicted by above- and belowground herbivores. Leaf herbivory increased Si concentrations in the leaves by >50% relative to herbivore-free plants, indicating it was an inducible defensive response. In plants without Si supplementation, leaf herbivory reduced shoot biomass by 52% and root herbivory reduced root biomass by 68%. Si supplementation, however, facilitated compensatory growth such that shoot losses were more than compensated for (+14% greater than herbivore-free plants) and root losses were minimised to -16%. Si supplementation did not improve plant resistance since Si did not enhance biomechanical resistance (i.e. force of fracture) or reduce leaf consumption and herbivore relative growth rates. We propose that Si-based defence operates in wheat via tolerance either in addition, or as an alternative, to resistance-based defence.

Data from: Nested species interactions promote feasibility over stability during the assembly of a pollinator community

The foundational concepts behind the persistence of ecological communities have been based on two ecological properties: dynamical stability and feasibility. The former is typically regarded as the capacity of a community to return to an original equilibrium state after a perturbation in species abundances and is usually linked to the strength of interspecific interactions. The latter is the capacity to sustain positive abundances on all its constituent species and is linked to both interspecific interactions and species demographic characteristics. Over the last 40 years, theoretical research in ecology has emphasized the search for conditions leading to the dynamical stability of ecological communities, while the conditions leading to feasibility have been overlooked. However, thus far, we have no evidence of whether species interactions are more conditioned by the community's need to be stable or feasible. Here, we introduce novel quantitative methods and use empirical data to investigate the consequences of species interactions on the dynamical stability and feasibility of mutualistic communities. First, we demonstrate that the more nested the species interactions in a community are, the lower the mutualistic strength that the community can tolerate without losing dynamical stability. Second, we show that high feasibility in a community can be reached either with high mutualistic strength or with highly nested species interactions. Third, we find that during the assembly process of a seasonal pollinator community located at The Zackenberg Research Station (northeastern Greenland), a high feasibility is reached through the nested species interactions established between newcomer and resident species. Our findings imply that nested mutualistic communities promote feasibility over stability, which may suggest that the former can be key for community persistence.

opencc-zeroDec 2017View details →

Data from: Matching habitat choice promotes species persistence under climate change

Species may survive under contemporary climate change by either shifting their range or adapting locally to the warmer conditions. Theoretical and empirical studies recently underlined that dispersal, the central mechanism behind these responses, may depend on the match between an individuals' phenotype and local environment. Such matching habitat choice is expected to induce an adaptive gene flow, but it now remains to be studied whether this local process could promote species' responses to climate change. Here, we investigate this by developing an individual-based model including either random dispersal or temperature-dependent matching habitat choice. We monitored population composition and distribution through space and time under climate change. Relative to random dispersal, matching habitat choice induced an adaptive gene flow that lessened spatial range loss during climate warming by improving populations' viability within the range (i.e. limiting range fragmentation) and by facilitating colonization of new habitats at the cold margin. The model even predicted in some cases range contraction under random dispersal but range expansion under optimal matching habitat choice. These benefits of matching habitat choice for population persistence mostly resulted from adaptive immigration decision and were greater for populations with larger dispersal distance and higher emigration probability. We also found that environmental stochasticity resulted in suboptimal matching habitat choice, decreasing the benefits of this dispersal mode under climate change. However population persistence was still better under suboptimal matching habitat choice than under random dispersal. Our results highlight the urgent need to implement more realistic mechanisms of dispersal such as matching habitat choice into models predicting the impacts of ongoing climate change on biodiversity.

Data from: Mating system plasticity promotes persistence and adaptation of colonizing populations of hermaphroditic angiosperms

Persistence and adaptation in novel environments are limited by small population size, strong selection, and maladaptive gene flow. Mating system plasticity is common in angiosperms and may provide both demographic and genetic benefits that promote niche evolution, including reproductive assurance and isolation from maladaptive gene flow. Yet increased self-fertilization may also cause inbreeding depression, accumulation of deleterious mutations, and reduced adaptive potential. Here we use individual-based simulations to examine the consequences of mating system plasticity for persistence and adaptation in a novel environment that imposes selection on a quantitative trait. We examine the joint evolution of local adaptation, inbreeding depression, and genetic load. We find that a plastic shift to a mixed mating system generally promotes niche evolution by decreasing the risk of extinction, providing isolation from maladaptive gene flow, and temporarily increasing genetic variance in the trait under selection, whereas obligate self-fertilization reduces adaptive potential. These effects are most pronounced under conditions of mate limitation, strong selection, or maladaptive gene flow. Our results highlight the diverse demographic and genetic consequences of self-fertilization and support the potential role for plastic shifts in mating system to promote niche evolution in flowering plants.

Data from: Ret and Etv4 promote directed movements of progenitor cells during renal branching morphogenesis

Branching morphogenesis of the epithelial ureteric bud forms the renal collecting duct system and is critical for normal nephron number, while low nephron number is implicated in hypertension and renal disease. Ureteric bud growth and branching requires GDNF signaling from the surrounding mesenchyme to cells at the ureteric bud tips, via the Ret receptor tyrosine kinase and coreceptor Gfrα1; Ret signaling up-regulates transcription factors Etv4 and Etv5, which are also critical for branching. Despite extensive knowledge of the genetic control of these events, it is not understood, at the cellular level, how renal branching morphogenesis is achieved or how Ret signaling influences epithelial cell behaviors to promote this process. Analysis of chimeric embryos previously suggested a role for Ret signaling in promoting cell rearrangements in the nephric duct, but this method was unsuited to study individual cell behaviors during ureteric bud branching. Here, we use Mosaic Analysis with Double Markers (MADM), combined with organ culture and time-lapse imaging, to trace the movements and divisions of individual ureteric bud tip cells. We first examine wild-type clones and then Ret or Etv4 mutant/wild-type clones in which the mutant and wild-type sister cells are differentially and heritably marked by green and red fluorescent proteins. We find that, in normal kidneys, most individual tip cells behave as self-renewing progenitors, some of whose progeny remain at the tips while others populate the growing UB trunks. In Ret or Etv4 MADM clones, the wild-type cells generated at a UB tip are much more likely to remain at, or move to, the new tips during branching and elongation, while their Ret−/− or Etv4−/− sister cells tend to lag behind and contribute only to the trunks. By tracking successive mitoses in a cell lineage, we find that Ret signaling has little effect on proliferation, in contrast to its effects on cell movement. Our results show that Ret/Etv4 signaling promotes directed cell movements in the ureteric bud tips, and suggest a model in which these cell movements mediate branching morphogenesis.

Data from: Eco-evolutionary feedback promotes Red Queen dynamics and selects for sex in predator populations

Although numerous hypotheses exist to explain the overwhelming presence of sexual reproduction across the tree of life, we still cannot explain its prevalence when considering all inherent costs involved. The Red Queen hypothesis states that sex is maintained because it can create novel genotypes with a selective advantage. This occurs when the interactions between species induce frequent environmental change. Here we investigate whether coevolution and eco-evolutionary feedback dynamics in a predator-prey system allows for indirect selection and maintenance of sexual reproduction in the predator. Combining models and chemostat experiments of a rotifer-algae system we show a continuous feedback between population and trait change along with recurrent shifts from selection by predation and competition for a limited resource. We found that a high propensity for sex was indirectly selected and was maintained in rotifer populations within environments containing these eco-evolutionary dynamics; whereas within environments under constant conditions, predators evolved rapidly to lower levels of sex. Thus, our results indicate that the influence of eco-evolutionary feedback dynamics on the overall evolutionary change has been underestimated.

opencc-zeroDec 2016View details →

Data from: Pioneer cells established by the [SWI+] prion can promote dispersal and out-crossing in yeast

To thrive in an ever-changing environment, microbes must widely distribute their progeny to colonize new territory. Simultaneously, they must evolve and adapt to the stresses of unpredictable surroundings. In both of these regards, diversity is key—if an entire population moved together or responded to the environment in the same way, it could easily go extinct. Here, we show that the epigenetic prion switch [SWI+] establishes a specialized subpopulation with a "pioneer" phenotypic program in Saccharomyces cerevisiae. Cells in the pioneer state readily disperse in water, enabling them to migrate and colonize new territory. Pioneers are also more likely to find and mate with genetically diverse partners, as inhibited mating-type switching causes mother cells to shun their own daughters. In the nonprion [swi−] state, cells instead have a "settler" phenotype, forming protective flocs and tending to remain in their current position. Settler cells are better able to withstand harsh conditions like drought and alkaline pH. We propose that these laboratory observations reveal a strategy employed in the wild to rapidly diversify and grant distinct, useful roles to cellular subpopulations that benefit the population as a whole.

Data from: Genetic loci inherited from hens lacking maternal behaviour both inhibit and paradoxically promote this behaviour

Background: A major step towards the success of chickens as a domesticated species was the separation between maternal care and reproduction. Artificial incubation replaced the natural maternal behaviour of incubation and, thus, in certain breeds, it became possible to breed chickens with persistent egg production and no incubation behaviour; a typical example is the White Leghorn strain. Conversely, some strains, such as the Silkie breed, are prized for their maternal behaviour and their willingness to incubate eggs. This is often colloquially known as broodiness. Results: Using an F2 linkage mapping approach and a cross between White Leghorn and Silkie chicken breeds, we have mapped, for the first time, genetic loci that affect maternal behaviour on chromosomes 1, 5, 8, 13, 18 and 19 and linkage group E22C19W28. Paradoxically, heterozygous and White Leghorn homozygous genotypes were associated with an increased incidence of incubation behaviour, which exceeded that of the Silkie homozygotes for most loci. In such cases, it is likely that the loci involved are associated with increased egg production. Increased egg production increases the probability of incubation behaviour occurring because egg laying must precede incubation. For the loci on chromosomes 8 and 1, alleles from the Silkie breed promote incubation behaviour and influence maternal behaviour (these explain 12 and 26 % of the phenotypic difference between the two founder breeds, respectively). Conclusions: The over-dominant locus on chromosome 5 coincides with the strongest selective sweep reported in chickens and together with the loci on chromosomes 1 and 8, they include genes of the thyrotrophic axis. This suggests that thyroid hormones may play a critical role in the loss of incubation behaviour and the improved egg laying behaviour of the White Leghorn breed. Our findings support the view that loss of maternal incubation behaviour in the White Leghorn breed is the result of selection for fertility and egg laying persistency and against maternal incubation behaviour.

Data from: Paired-end analysis of transcription start sites in Arabidopsis reveals plant-specific promoter signatures

Understanding plant gene promoter architecture has long been a challenge due to the lack of relevant large-scale data sets and analysis methods. Here, we present a publicly available, large-scale transcription start site (TSS) data set in plants using a high-resolution method for analysis of 5′ ends of mRNA transcripts. Our data set is produced using the paired-end analysis of transcription start sites (PEAT) protocol, providing millions of TSS locations from wild-type Columbia-0 Arabidopsis thaliana whole root samples. Using this data set, we grouped TSS reads into "TSS tag clusters" and categorized clusters into three spatial initiation patterns: narrow peak, broad with peak, and weak peak. We then designed a machine learning model that predicts the presence of TSS tag clusters with outstanding sensitivity and specificity for all three initiation patterns. We used this model to analyze the transcription factor binding site content of promoters exhibiting these initiation patterns. In contrast to the canonical notions of TATA-containing and more broad "TATA-less" promoters, the model shows that, in plants, the vast majority of transcription start sites are TATA free and are defined by a large compendium of known DNA sequence binding elements. We present results on the usage of these elements and provide our Plant PEAT Peaks (3PEAT) model that predicts the presence of TSSs directly from sequence.

opencc-zeroDec 2017View details →

Data from: Human disturbance promotes herbivory by leaf-cutting ants in the Caatinga dry forest

Anthropogenic disturbances are known to modify plant-animal interactions such as those involving the leaf-cutting ants, the most voracious and proliferating herbivore across human-modified landscapes in the Neotropics. Here we evaluate the effect of chronic anthropogenic disturbance (e.g. firewood collection, livestock grazing) and vegetation seasonality on foraging area, foliage availability in the foraging area, leaf consumption, and herbivory rate of the leaf-cutting ant Atta opaciceps in the semi-arid Caatinga, a mosaic of dry forest and scrub vegetation in northeast Brazil. Contrary to our initial expectation, the foraging area was not affected by either disturbance intensity or the interaction between season and disturbance intensity. However, leaf consumption and herbivory rate were higher in more disturbed areas. We also found a strong effect of seasonality, with higher leaf consumption and herbivory rate in the dry season. Our results suggest that the foraging ecology of leaf-cutting ants is modulated by human disturbance and seasonality as these two drivers affect the spectrum and the amount of resources available for these ants in the Caatinga. Despite the low productivity of Caatinga vegetation, the annual rates of biomass consumption by A. opaciceps are similar to those reported from other leaf-cutting ants in rainforests and savannas. This is made possible by maintaining high foraging activity even in the peak of the dry season and taking benefit from any resource available, including low-quality items. Such compensation highlights the adaptive capacity of LCA to persist or even proliferate in human-modified landscapes from dry to rainforests.

Data from: Does adaptive radiation of a host lineage promote ecological diversity of its bacterial communities? A test using gut microbiota of Anolis lizards

Adaptive radiations provide unique opportunities to test whether and how recent ecological and evolutionary diversification of host species structures the composition of entire bacterial communities. We used 16S rRNA gene sequencing of faecal samples to test for differences in the gut microbiota of six species of Puerto Rican Anolis lizards characterized by the evolution of distinct 'ecomorphs' related to differences in habitat use. We found substantial variation in the composition of the microbiota within each species and ecomorph (trunk-crown, trunk-ground, grass-bush), but no differences in bacterial alpha diversity among species or ecomorphs. Beta diversity analyses revealed subtle but significant differences in bacterial composition related to host phylogeny and species, but these differences were not consistently associated with Anolis ecomorph. Comparison of a trunk-ground species from this clade (A. cristatellus) with a distantly related member of the same ecomorph class (A. sagrei) where the two species have been introduced and are now sympatric in Florida revealed pronounced differences in the alpha diversity and beta diversity of their microbiota despite their ecological similarity. Comparisons of these populations with allopatric conspecifics also revealed geographic differences in bacterial alpha diversity and beta diversity within each species. Finally, we observed high intraindividual variation over time and strong effects of a simplified laboratory diet on the microbiota of A. sagrei. Collectively, our results indicate that bacterial communities are only weakly shaped by the diversification of their lizard hosts due to the strikingly high levels of bacterial diversity and variation observed within Anolis species.

opencc-zeroDec 2014View details →

Data from: Monoallelic loss of the imprinted gene Grb10 promotes tumor formation in irradiated Nf1+/- mice

Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis.

Data from: TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation

The functions of the TAF subunits of mammalian TFIID in physiological processes remain poorly characterised. Here we describe a novel function of TAFs in directing genomic occupancy of a transcriptional activator. Using liver-specific inactivation in mice, we show that the TAF4 subunit of TFIID is required for post-natal hepatocyte maturation. TAF4 promotes pre-initiation complex (PIC) formation at post-natal expressed liver function genes and down-regulates a subset of embryonic expressed genes by increased RNA polymerase II pausing. The TAF4-TAF12 heterodimer interacts directly with HNF4A and in vivo TAF4 is necessary to maintain HNF4A-directed embryonic gene expression at post-natal stages and promotes HNF4A occupancy of functional cis-regulatory elements adjacent to the transcription start sites of post-natal expressed genes. Stable HNF4A occupancy of these regulatory elements requires TAF4-dependent PIC formation highlighting that these are mutually dependent events. Local promoter-proximal HNF4A-TFIID interactions therefore act as instructive signals for post-natal hepatocyte differentiation.