Miracle-dz/UniFAR-FTUs huggingface dataset:
The INO80 remodeler couples premature termination of mRNA synthesis with transcription elongation

RNA quality control and timely termination of aberrant transcription are critical for functional gene expression. Here, we report that in Saccharomyces cerevisiae premature transcription termination of mRNAs is coordinated with the transcriptional elongation process and regulated by the evolutionarily conserved ATP-dependent chromatin remodeling complex INO80. Loss of INO80 sensitizes cells to the transcriptional elongation stress drug 6-azauracil and leads to enhanced pausing of elongating RNA Polymerase II across the genome. Transcriptional pausing positively correlates with premature termination of mRNA transcription and is pronounced proximally to promoters at sites of enhanced histone H3 binding to DNA. Cells with deficient INO80 complex accumulate short, unproductive mRNA transcripts on chromatin and are defective in transcription termination mediated by the Nrd1-Nab3-Sen1 (NNS) complex. We find that loss of INO80 compromises the interaction of the RNA surveillance factor Nab2 with short promoter-proximal mRNA transcripts. INO80 promotes co-transcriptional recruitment of Nab2 to chromatin by enabling its interaction with the histone variant H2A.Z. Finally, inactivation of the histone deacetylase complex Rpd3S/Rco1 reduces promoter-proximal pausing and enhances productive transcription through an NNS-dependent termination site when INO80 is compromised. Our work suggests that, by regulation of H2A.Z-containing nucleosomes, INO80 orchestrates a mechanism for premature transcription termination, linking RNA quality control to the transcriptional process.
Development of nascent focal adhesions in spreading cells

Cell spreading provides one of the simplest configurations in which eukaryotic cells develop angular symmetry-breaking assemblies of mechanosensing and mechanotransducive organelles in preparation for cell differentiation and movement. By identifying the edge of the cell-ECM adhesion area as having an important role in mechanosensor complex aggregation, we consider the spatial patterns arising on this edge, within a 1D lattice model of the nearest-neighbour interaction between individual integrin-mediated mechanosensors. We obtain the Ginzburg-Landau free energy for this model and analyse the spectrum of spatial modes as the cell spreads and increases the contact area. We test the plausibility of our model by comparing its predictions for the azimuthal angular frequency of aggregation of mechanosensors into nascent focal adhesions (FAs) to observations of the paxillin distribution in spreading fibroblasts. STATEMENT OF SIGNIFICANCE The topic of cell adhesion on substrates is very active, with numerous theoretical, experimental and computer simulation studies probing the mechanisms and signalling pathways of cell response to interacting with substrate. Integrin-based adhesion complexes are known to be the individual units of this process, and their dense aggregation into focal adhesions leads to cells developing asymmetry, polarity, and eventually - locomotion. Here we develop a theoretical model that suggests that physical interactions between individual adhesion complexes is the factor that defines the initial breaking of symmetry of the cell spreading on substrate, and predicts the characteristic wavelength of modulation above the critical size of adhesion area.
Identification of X-chromosomal genes that drive global X-dosage effects in mouse embryonic stem cells

X-chromosomal genes contribute to sex differences, in particular during early development, when both X chromosomes are active in females. Here, double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting the differentiation-promoting MAP kinase (MAPK) signalling pathway and delaying differentiation. To identify the genetic basis of these sex differences, we have performed a series of CRISPR knockout screens in murine embryonic stem cells to comprehensively identify X-linked genes that cause the female pluripotency phenotype. We found multiple genes that act in concert, among which Klhl13 plays a central role. We show that this E3 ubiquitin ligase substrate adaptor protein promotes pluripotency factor expression, delays differentiation and represses MAPK target genes, and we identify putative substrates. We thus elucidate the mechanisms that drive sex-induced differences in pluripotent cells with implications for gender medicine in the context of induced pluripotent stem cell based therapies.
Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease

Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia and is associated with a host of health complications including dementia, diabetes, heart failure, and stroke. Although the lung is the first organ to sense changes in inspired oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor (HIF)-responsive pathways. Furthermore, cellular mechanisms causing disease progression across multiple systems in OSA are unknown. We hypothesized that exposure to IH would lead to up- and down-regulation of diverse expression pathways and that individual cell populations would show distinctive responses to IH. We identify changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells show the most prominent transcriptional changes. Interestingly, up-regulated genes in endothelial, fibroblast, and myofibroblast cells were enriched for genes associated with pulmonary fibrosis and pulmonary hypertension. These genes include targets of several drugs currently used to treat chronic pulmonary diseases. Our results reveal potential candidates for cell-targeted therapy seeking to minimize pulmonary effects of OSA. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.
Protein QTL analysis of IGF-I and its binding proteins provides insights into growth biology

The growth hormone and insulin-like growth factor (IGF) system is integral to human growth. Genome-wide association studies (GWAS) have identified variants associated with height and located near the genes in this pathway. However, mechanisms underlying these genetic associations are not understood. To investigate the regulation of the genes in this pathway and mechanisms by which regulation could affect growth, we performed GWAS of measured serum protein levels of IGF-I, IGFBP-3, PAPP-A2, IGF-II, and IGFBP-5 in 839 children (3-18 years) from the Cincinnati Genomic Control Cohort. We identified variants associated with protein levels near IGFBP3 and IGFBP5 genes, which contain multiple signals of association with height and other skeletal growth phenotypes. Surprisingly, variants that associate with protein levels at these two loci do not colocalize with height associations, confirmed through conditional analysis. Rather, the IGFBP3 signal (associated with total IGFBP-3 and IGF-II levels) colocalizes with an association with sitting height ratio (SHR); the IGFBP5 signal (associated with IGFBP-5 levels) colocalizes with birth weight. Indeed, height-associated SNPs near genes encoding other proteins in this pathway are not associated with serum levels, possibly excluding PAPP-A2. Mendelian randomization supports a stronger relationship of measured serum levels with SHR (for IGFBP-3) and birth weight (for IGFBP-5) than with height. In conclusion, we begin to characterize the genetic regulation of serum levels of IGF-related proteins in childhood. Furthermore, our data strongly suggest the existence of growth-regulating mechanisms acting through IGF-related genes in ways that are not reflected in measured serum levels of the corresponding proteins.
Structural Disconnection of the Tool Use Network after Left Hemisphere Stroke Predicts Limb Apraxia Severity

Producing a tool use gesture is a complex process drawing upon the integration of stored knowledge of tools and their associated actions with sensory-motor mechanisms supporting the planning and control of hand and arm actions. Understanding how sensory-motor systems in parietal cortex interface with semantic representations of actions and objects in the temporal lobe remains a critical issue, and is hypothesized to be a key determinant of the severity of limb apraxia, a deficit in producing skilled action after left hemisphere stroke. We used voxel-based and connectome-based lesion symptom mapping with data from 57 left hemisphere stroke participants to assess the lesion sites and structural disconnection patterns associated with poor tool use gesturing. We found that structural disconnection between the left inferior parietal lobule, lateral temporal lobe (left middle temporal gyrus) and ventral temporal cortex (left medial fusiform gyrus) predicted the severity of tool use gesturing performance. Control analyses demonstrated that reductions in right-hand grip strength were associated with motor system disconnection, bypassing regions supporting tool use gesturing. Our findings provide causal evidence that limb apraxia may arise, in part, from disconnection of conceptual representations in the temporal lobe from mechanisms enabling skilled action production in the inferior parietal lobule.
A metabolic shift to glycolysis promotes zebrafish tail regeneration through TGF–β dependent dedifferentiation of notochord cells to form the blastema

Mammals are generally poor at tissue regeneration, in contrast, fish maintain a high capacity for regenerating complex tissues after injury. Using larval zebrafish, we show that tail amputation triggers an metabolic shift to glycolysis in cells surrounding the notochord as they reposition to the amputation site. Blocking glycolysis prevents the fin from regenerating after amputation due to the failure to form a normal, pluripotent blastema. We performed a time series of scRNA-sequencing on regenerating tails under normal conditions or in the absence of glycolysis. Strikingly, we detected a transient cell population in the single cell analysis that represents notochord sheath cells undergoing a TGF–β dependent dedifferentiation and epithelium-to-mesenchyme transition to become pluripotent blastema cells. We further demonstrated that the metabolic switch to glycolysis is required for TGF–β signaling and blocking either glycolysis or TGF–β receptors results in aberrant blastema formation through the suppression of essential EMT mediators such as snai1.
Management implications based on diversity patterns under climate change scenarios in a continental island biodiversity hotspot

In the Anthropocene era, climate change poses a great challenge in environmental management and decision-making for species and habitat conservation. To support decision-making, many studies exist regarding the expected vegetation changes and the impacts of climate change on European plants, yet none has investigated how climate change will affect the extinction risk of the entire endemic flora of an island biodiversity hotspot, with intense human disturbance. Our aim is to assess, in an integrated manner, the impact of climate change on the biodiversity and biogeographical patterns of Crete and to provide a case-study upon which a cost-effective and climate-smart conservation planning strategy might be set. We employed a variety of macroecological analyses and estimated the current and future biodiversity, conservation and extinction hotspots in Crete, as well as the factors that may have shaped these distribution patterns. We also evaluated the effectiveness of climate refugia and the NATURA 2000 network (PAs) on protecting the most vulnerable species and identified the taxa that should be of conservation priority based on the Evolutionary Distinct and Globally Endangered (EDGE) index, during any environmental management process. The highlands of Cretan mountain massifs have served as both diversity cradles and museums, due to their stable climate and high topographical heterogeneity. They are also identified as biodiversity hotspots, as well as areas of high conservation and evolutionary value, due their high EDGE scores. Due to the ‘escalator to extinction’ phenomenon and the subsequent biotic homogenization, these areas are projected to become diversity ‘death-zones’ in the near future and should thus be prioritized in terms of conservation efforts and by decision makers. In-situ conservation focusing at micro-reserves and ex-situ conservation practices should be considered as an insurance policy against such biodiversity losses, which constitute cost-effective conservation measures. Scientists and authorities should aim the conservation effort at areas with overlaps among PAs and climate refugia, characterized by high diversity and EDGE scores. These areas may constitute Anthropocene refugia. Thus, this climate-smart, cost-effective conservation-prioritization planning will allow the preservation of evolutionary heritage, trait diversity and future services for human well-being and acts as a pilot for similar regions worldwide.
Cancer Stem Cell Enrichment and Metabolic Substrate Adaptability are Driven by Hydrogen Sulfide Suppression in Glioblastoma

Glioblastoma (GBM) remains among the deadliest of human malignancies. The emergence of the cancer stem cell (CSC) phenotype represents a major challenge to disease management and durable treatment response. The extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. The CSC state endows cells with a fluid metabolic profile, enabling the utilization of multiple nutrient sources. Therefore, to test the impact of diet on CSC enrichment, we evaluated disease progression in tumor-bearing mice fed an obesity-inducing high-fat diet (HFD) versus an energy-balanced, low-fat control diet. HFD consumption resulted in hyper-aggressive disease that was accompanied by CSC enrichment and shortened survival. HFD consumption also drove intracerebral accumulation of saturated fats, which in turn inhibited the production and signaling of the gasotransmitter hydrogen sulfide (H2S). H2S is an endogenously produced bio-active metabolite derived from sulfur amino acid catabolism. It functions principally through protein S-sulfhydration and regulates a variety of programs including mitochondrial bioenergetics and cellular metabolism. Inhibition of H2S synthesis resulted in increased proliferation and chemotherapy resistance, whereas treatment with H2S donors led to cytotoxicity and death of cultured GBM cells. Compared to non-cancerous controls, patient GBM specimens were reduced in overall protein S-sulfhydration, which was primarily lost from proteins regulating cellular metabolism. These findings support the hypothesis that diet-regulated H2S signaling serves to suppress GBM by restricting metabolic adaptability, while its loss triggers CSC enrichment and disease acceleration. Interventions augmenting H2S bioavailability concurrent with GBM standard of care may improve outcomes for GBM patients. One Sentence Summary Consumption of a high-fat diet (HFD) accelerates glioblastoma (GBM) by inhibiting the production and signaling of the tumor-suppressive metabolite hydrogen sulfide (H2S).
Nucleolar stress causes the entry into replicative senescence in budding yeast

The accumulation of Extrachromosomal rDNA Circles (ERCs) and their asymmetric segregation upon division have been hypothesized to be responsible for replicative senescence in mother yeasts and rejuvenation in daughter cells. However, it remains unclear by which molecular mechanisms ERCs would trigger the irreversible cell cycle slow-down leading to cell death. We show that ERCs accumulation is concomitant with a nucleolar stress, characterized by a massive accumulation of pre-rRNAs in the nucleolus, leading to a loss of nucleus-to-cytoplasm ratio, decreased growth rate and cell-cycle slow-down. This nucleolar stress, observed in old mothers, is not inherited by rejuvenated daughters. Unlike WT, in the long-lived mutant fob1∆, a majority of cells is devoid of nucleolar stress and does not experience replicative senescence before death. Our study provides a unique framework to order the successive steps that govern the transition to replicative senescence and highlights the causal role of nucleolar stress in cellular aging.
Pod and Seed Trait QTL Identification To Assist Breeding for Peanut Market Preferences

Although seed and pod traits are important for peanut breeding, little is known about the inheritance of these traits. A recombinant inbred line (RIL) population of 156 lines from a cross of Tifrunner x NC 3033 was genotyped with the Axiom_Arachis1 SNP array and SSRs to generate a genetic map composed of 1524 markers in 29 linkage groups (LG). The genetic positions of markers were compared with their physical positions on the peanut genome to confirm the validity of the linkage map and explore the distribution of recombination and potential chromosomal rearrangements. This linkage map was then used to identify Quantitative Trait Loci (QTL) for seed and pod traits that were phenotyped over three consecutive years for the purpose of developing trait-associated markers for breeding. Forty-nine QTL were identified in 14 LG for seed size index, kernel percentage, seed weight, pod weight, single-kernel, double-kernel, pod area and pod density. Twenty QTL demonstrated phenotypic variance explained (PVE) greater than 10% and eight more than 20%. Of note, seven of the eight major QTL for pod area, pod weight and seed weight (PVE >20% variance) were attributed to NC 3033 and located in a single linkage group, LG B06_1. In contrast, the most consistent QTL for kernel percentage were located on A07/B07 and derived from Tifrunner.
Establishment of a marine nematode model for animal functional genomics, environmental adaptation and developmental evolution

Nematodes play key roles in marine ecosystem. Although oceans cover 71% of the Earth’s surface, none of marine model nematode has been reported. Here, we constructed the first inbred line of free-living marine nematode Litoditis marina, sequenced and assembled its genome. Furthermore, we successfully applied CRISPR/Cas9 genome editing in L. marina. Comparative genomics revealed that immunity and oxygen regulation genes are expanded, which is probably central to its sediment adaptation. While L. marina exhibits massive gene contractions in NHRs, chemoreceptors, xenobiotics detoxification and core histones, which could explain the more defined marine environment. Our experiments showed that dozens of H4 genes in Caenorhabditis elegans might contribute to its adaptation to the complex terrestrial environments, while two H4 genes in L. marina are involved in salinity stress adaptation. Additionally, ninety-two conserved genes appear to be positively selected in L. marina, which may underpin its osmotic, neuronal and epigenetic changes in the sea. With short generation time, highly inbred lines, and genomic resources, our report brings L. marina a promising marine animal model, and a unique satellite marine model to the well-known biomedical model nematode C. elegans. This study will underpin ongoing work on animal functional genomics, environmental adaptation and developmental evolution.
Autoregulation clamps the synaptic membrane-remodeling machinery and promotes productive actin-dependent endocytosis

Synaptic membrane-remodeling events such as endocytosis require force-generating actin assembly. The endocytic machinery that regulates these actin and membrane dynamics localizes at high concentrations in a micron-scale synaptic membrane domain called the ‘periactive zone’ (PAZ). Paradoxically, endocytic events occur only sparsely in space and time within the PAZ. Here we describe a mechanism whereby autoinhibition clamps the PAZ machinery to limit actin assembly to discrete functional events. We found that collective interactions between the Drosophila PAZ proteins Nwk/FCHSD2, Dap160/Intersectin, and WASp relieve Nwk autoinhibition and promote robust membrane-coupled actin assembly in vitro. Using automated particle tracking to quantify synaptic actin dynamics in vivo, we discovered that Nwk-Dap160 interactions constrain spurious assembly of WASp-dependent actin structures. These interactions also promote synaptic endocytosis, suggesting that autoinhibition both clamps and primes the synaptic endocytic machinery, thereby constraining actin assembly to drive productive membrane remodeling in response to physiological cues.
Correlated evolution of large DNA fragments in the chromatin interaction network: a case study in Arabidopsis thaliana

In eukaryotes, the three-dimensional (3D) conformation of the genome is far from random, and this nonrandom chromatin organization is strongly correlated with gene expression and protein function, which are two critical determinants of the selective constraints and evolutionary rates of genes. However, whether genes and other elements that are located close to each other in the 3D genome evolve in a coordinated way has not been investigated in any organism. To address this question, we constructed chromatin interaction networks (CINs) in Arabidopsis thaliana based on high-throughput chromosome conformation capture (Hi-C) data and demonstrated that adjacent large DNA fragments in the CIN indeed exhibit more similar levels of polymorphism and evolutionary rates than random fragment pairs. Using simulations that account for the linear distance between fragments, we proved that the 3D chromosomal organization plays a role in the observed correlated evolution. Interacting Hi-C fragments also exhibit more similar mutation rates and functional constraints in both coding and noncoding regions than the random expectations, indicating that the coordinated evolution between 3D neighbors is a result of combined evolutionary forces. A collection of 39 genomic and epigenomic features can explain much of the variance in genetic diversity and evolutionary rates across the genome. Moreover, features that have a greater effect on the evolution of regional sequences tend to show higher similarity between neighboring fragments in the CIN, suggesting a pivotal role of epigenetic modifications and chromatin organization in determining the correlated evolution of large DNA fragments in the 3D genome.
Nanopore long-read transcriptome data of fungal pathogen of chalkbrood disease, Ascosphaera apis

Ascosphaera apis is a fungal pathogen that exclusively infects honeybee larvae, leading to chalkbrood disease, which damages the number of adult honeybees and colony productivity. In this article, A. apis mecylia and spores were respectively purified followed by Oxford Nanopore sequencing via PromethION platform. In total, 6,321,704 and 6,259,727 raw reads were generated from Aam and Aas, with a length distribution among 1 kb~10 kb. The quality (Q) scores of majority of raw reads were Q9 (Aam) and Q11 (Aas). Additionally, 5,669,436 and 6,233,159 clean reads were gained, among them 79.32% and 79.62% were identified as being full-length. The lengths of redundant reads-removed full-length transcripts were among 1 kb~8 kb and 1 kb~9 kb, and most abundant length for both was 1 kb. Furthermore, the length of redundant transcripts-removed clean reads was ranged from 1 kb~7 kb, with the largest group of 1 kb. The data reported here provides a beneficial genetic resource for improving genome and transcriptome annotations of A. apis and for exploring alternative splicing and polyadenylation of A. apis mRNAs. Value of the result Current dataset enables better understanding of the complexity of A. apis transcriptome. The long-read transcriptome data can be used to identify of genes and transcripts associated with A. apis infection mechanism. The accessible data provides full-length transcripts for improving gene structure and functional annotation of A. apis transcriptome. This dataset could be utilized for investigation of alternative splicing and polyadenylation of A. apis mRNAs.