A phosphate starvation response-centered network regulates mycorrhizal symbiosis.

To secure phosphorus (P) from soil, most land plants use a direct phosphate uptake pathway via root hairs and epidermis and an indirect phosphate uptake pathway via mycorrhizal symbiosis. The interaction between these two pathways is unclear. Here, we mapped a network between transcription factors and mycorrhizal symbiosis-related genes using Y1H. Intriguingly, this gene regulatory network is governed by the conserved P-sensing pathway, centered on phosphate starvation response (PHR) transcription factors. PHRs are required for mycorrhizal symbiosis and regulate symbiosis-related genes via the P1BS motif. SPX-domain proteins suppress OsPHR2-mediated induction of symbiosis-related genes and inhibit mycorrhizal infection. In contrast, plants overexpressing OsPHR2 show improved mycorrhizal infection and are partially resistant to P-mediated inhibition of symbiosis. Functional analyses of network nodes revealed co-regulation of hormonal signaling and mycorrhizal symbiosis. This network deciphers extensive regulation of mycorrhizal symbiosis by endogenous and exogenous signals and highlights co-option of the P-sensing pathway for mycorrhizal symbiosis.

On the origins of developmental robustness: modeling buffering mechanisms against cell-level noise.

During development, cells are subject to stochastic fluctuations in their positions (i.e. cell-level noise) that can potentially lead to morphological noise (i.e. stochastic differences between morphologies that are expected to be equal, e.g. the right and left sides of bilateral organisms). In this study, we explore new and existing hypotheses on buffering mechanisms against cell-level noise. Many of these hypotheses focus on how the boundaries between territories of gene expression remain regular and well defined, despite cell-level noise and division. We study these hypotheses and how irregular territory boundaries lead to morphological noise. To determine the consistency of the different hypotheses, we use a general computational model of development: EmbryoMaker. EmbryoMaker can implement arbitrary gene networks regulating basic cell behaviors (contraction, adhesion, etc.), signaling and tissue biomechanics. We found that buffering mechanisms based on the orientation of cell divisions cannot lead to regular boundaries but that other buffering mechanisms can (homotypic adhesion, planar contraction, non-dividing boundaries, constant signaling and majority rule hypotheses). We also explore the effects of the shape and size of the territories on morphological noise.

Community cohesion looseness in gene networks reveals individualized drug targets and resistance.

Community cohesion plays a critical role in the determination of an individual's health in social science. Intriguingly, a community structure of gene networks indicates that the concept of community cohesion could be applied between the genes as well to overcome the limitations of single gene-based biomarkers for precision oncology. Here, we develop community cohesion scores which precisely quantify the community ability to retain the interactions between the genes and their cellular functions in each individualized gene network. Using breast cancer as a proof-of-concept study, we measure the community cohesion score profiles of 950 case samples and predict the individualized therapeutic targets in 2-fold. First, we prioritize them by finding druggable genes present in the community with the most and relatively decreased scores in each individual. Then, we pinpoint more individualized therapeutic targets by discovering the genes which greatly contribute to the community cohesion looseness in each individualized gene network. Compared with the previous approaches, the community cohesion scores show at least four times higher performance in predicting effective individualized chemotherapy targets based on drug sensitivity data. Furthermore, the community cohesion scores successfully discover the known breast cancer subtypes and we suggest new targeted therapy targets for triple negative breast cancer (e.g. KIT and GABRP). Lastly, we demonstrate that the community cohesion scores can predict tamoxifen responses in ER+ breast cancer and suggest potential combination therapies (e.g. NAMPT and RXRA inhibitors) to reduce endocrine therapy resistance based on individualized characteristics. Our method opens new perspectives for the biomarker development in precision oncology.

The GATA factor ELT-3 specifies endoderm in Caenorhabditis angaria in an ancestral gene network.

Endoderm specification in Caenorhabditis elegans occurs through a network in which maternally provided SKN-1/Nrf, with additional input from POP-1/TCF, activates the GATA factor cascade MED-1,2→END-1,3→ELT-2,7. Orthologues of the MED, END and ELT-7 factors are found only among nematodes closely related to C. elegans, raising the question of how gut is specified in their absence in more distant species in the genus. We find that the C. angaria, C. portoensis and C. monodelphis orthologues of the GATA factor gene elt-3 are expressed in the early E lineage, just before their elt-2 orthologues. In C. angaria, Can-pop-1(RNAi), Can-elt-3(RNAi) and a Can-elt-3 null mutation result in a penetrant 'gutless' phenotype. Can-pop-1 is necessary for Can-elt-3 activation, showing that it acts upstream. Forced early E lineage expression of Can-elt-3 in C. elegans can direct the expression of a Can-elt-2 transgene and rescue an elt-7 end-1 end-3; elt-2 quadruple mutant strain to viability. Our results demonstrate an ancestral mechanism for gut specification and differentiation in Caenorhabditis involving a simpler POP-1→ELT-3→ELT-2 gene network.

CoRegNet: unraveling gene co-regulation networks from public RNA-Seq repositories using a beta-binomial statistical model.

Millions of RNA sequencing samples have been deposited into public databases, providing a rich resource for biological research. These datasets encompass tens of thousands of experiments and offer comprehensive insights into human cellular regulation. However, a major challenge is how to integrate these experiments that acquired at different conditions. We propose a new statistical tool based on beta-binomial distributions that can construct robust gene co-regulation network (CoRegNet) across tens of thousands of experiments. Our analysis of over 12 000 experiments involving human tissues and cells shows that CoRegNet significantly outperforms existing gene co-expression-based methods. Although the majority of the genes are linearly co-regulated, we did discover an interesting set of genes that are non-linearly co-regulated; half of the time they change in the same direction and the other half they change in the opposite direction. Additionally, we identified a set of gene pairs that follows the Simpson's paradox. By utilizing public domain data, CoRegNet offers a powerful approach for identifying functionally related gene pairs, thereby revealing new biological insights.

Epigenetic factor competition reshapes the EMT landscape.

The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene-regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as gene-regulatory networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. In this paper, we propose a conceptual and mathematical modeling framework that incorporates both local and global competition effects between antagonistic epigenetic regulators, in addition to local transcription factors, and show the counterintuitive consequences of such interactions. We apply our approach to recent experimental findings on the epithelial-mesenchymal transition (EMT). We show that it can explain the puzzling experimental data, as well as provide verifiable predictions.

The master regulator for entry into sporulation in Bacillus subtilis becomes a mother cell-specific transcription factor for forespore engulfment.

The Spo0A transcription factor is activated by phosphorylation in starving Bacillus subtilis cells. The activated Spo0A (Spo0A~P) regulates genes controlling entry into sporulation and appears to control mother-cell-specific gene expression after asymmetric division, but the latter remains elusive. Here, we found that Spo0A~P directly binds to three conserved DNA sequences (0A1-3) in the promoter region of the mother cell-specific lytic transglycosylase gene spoIID, which is transcribed by σE -RNA polymerase (RNAP) and negatively controlled by the SpoIIID transcription factor and required for forespore engulfment. Systematic mutagenesis of the 0A boxes revealed that the 0A1 and 0A2 boxes located upstream of the promoter positively control the transcription of spoIID. In contrast, the 0A3 box located downstream of the promoter negatively controls the transcription of spoIID. The mutated SpoIIID binding site located between the -35 and -10 promoter elements causes increased expression of spoIID and reduced sporulation. When the mutations of 0A1, 0A2, and IIID sites are combined, sporulation is restored. Collectively, our data suggest that the mother cell-specific spoIID expression is precisely controlled by the coordination of three factors, Spo0A~P, SpoIIID, and σE -RNAP, for proper sporulation. The conservation of this mechanism across spore-forming species was discussed.

An integrated brain-specific network identifies genes associated with neuropathologic and clinical traits of Alzheimer's disease.

Alzheimer's disease (AD) has a strong genetic predisposition. However, its risk genes remain incompletely identified. We developed an Alzheimer's brain gene network-based approach to predict AD-associated genes by leveraging the functional pattern of known AD-associated genes. Our constructed network outperformed existing networks in predicting AD genes. We then systematically validated the predictions using independent genetic, transcriptomic, proteomic data, neuropathological and clinical data. First, top-ranked genes were enriched in AD-associated pathways. Second, using external gene expression data from the Mount Sinai Brain Bank study, we found that the top-ranked genes were significantly associated with neuropathological and clinical traits, including the Consortium to Establish a Registry for Alzheimer's Disease score, Braak stage score and clinical dementia rating. The analysis of Alzheimer's brain single-cell RNA-seq data revealed cell-type-specific association of predicted genes with early pathology of AD. Third, by interrogating proteomic data in the Religious Orders Study and Memory and Aging Project and Baltimore Longitudinal Study of Aging studies, we observed a significant association of protein expression level with cognitive function and AD clinical severity. The network, method and predictions could become a valuable resource to advance the identification of risk genes for AD.

A Data-Driven Computational Framework for Assessing the Risk of Placental Exposure to Environmental Chemicals.

A computational framework based on placental gene networks was proposed in this work to improve the accuracy of the placental exposure risk assessment of environmental compounds. The framework quantitatively characterizes the ability of compounds to cross the placental barrier by systematically considering the interaction and pathway-level information on multiple placental transporters. As a result, probability scores were generated for 307 compounds crossing the placental barrier based on this framework. These scores were then used to categorize the compounds into different levels of transplacental transport range, creating a gradient partition. These probability scores not only facilitated a more intuitive understanding of a compound's ability to cross the placental barrier but also provided valuable information for predicting potential placental disruptors. Compounds with probability scores greater than 90% were considered to have significant transplacental transport potential, whereas those with probability scores less than 80% were classified as unlikely to cross the placental barrier. Furthermore, external validation set results showed that the probability score could accurately predict the compounds known to cross the placental barrier. In conclusion, the computational framework proposed in this study enhances the intuitive understanding of the ability of compounds to cross the placental barrier and opens up new avenues for assessing the placental exposure risk of compounds.

In silico exploration of anti-prostate cancer compounds from differential expressed genes.

Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol-1) and pimozide binding to HERG (-7.636 kcal.mol-1). Overall, binding energy ΔGbind (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol-1) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol-1). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.

Geometry of gene regulatory dynamics.

Embryonic development leads to the reproducible and ordered appearance of complexity from egg to adult. The successive differentiation of different cell types that elaborate this complexity results from the activity of gene networks and was likened by Waddington to a flow through a landscape in which valleys represent alternative fates. Geometric methods allow the formal representation of such landscapes and codify the types of behaviors that result from systems of differential equations. Results from Smale and coworkers imply that systems encompassing gene network models can be represented as potential gradients with a Riemann metric, justifying the Waddington metaphor. Here, we extend this representation to include parameter dependence and enumerate all three-way cellular decisions realizable by tuning at most two parameters, which can be generalized to include spatial coordinates in a tissue. All diagrams of cell states vs. model parameters are thereby enumerated. We unify a number of standard models for spatial pattern formation by expressing them in potential form (i.e., as topographic elevation). Turing systems appear nonpotential, yet in suitable variables the dynamics are low dimensional and potential. A time-independent embedding recovers the original variables. Lateral inhibition is described by a saddle point with many unstable directions. A model for the patterning of the Drosophila eye appears as relaxation in a bistable potential. Geometric reasoning provides intuitive dynamic models for development that are well adapted to fit time-lapse data.

Experimental competition induces immediate and lasting effects on the neurogenome in free-living female birds.

Periods of social instability can elicit adaptive phenotypic plasticity to promote success in future competition. However, the underlying molecular mechanisms have primarily been studied in captive and laboratory-reared animals, leaving uncertainty as to how natural competition among free-living animals affects gene activity. Here, we experimentally generated social competition among wild, cavity-nesting female birds (tree swallows, Tachycineta bicolor). After territorial settlement, we reduced the availability of key breeding resources (i.e., nest boxes), generating heightened competition; within 24 h we reversed the manipulation, causing aggressive interactions to subside. We sampled females during the peak of competition and 48 h after it ended, along with date-matched controls. We measured transcriptomic and epigenomic responses to competition in two socially relevant brain regions (hypothalamus and ventromedial telencephalon). Gene network analyses suggest that processes related to energy mobilization and aggression (e.g., dopamine synthesis) were up-regulated during competition, the latter of which persisted 2 d after competition had ended. Cellular maintenance processes were also down-regulated after competition. Competition additionally altered methylation patterns, particularly in pathways related to hormonal signaling, suggesting those genes were transcriptionally poised to respond to future competition. Thus, experimental competition among free-living animals shifts gene expression in ways that may facilitate the demands of competition at the expense of self-maintenance. Further, some of these effects persisted after competition ended, demonstrating the potential for epigenetic biological embedding of the social environment in ways that may prime individuals for success in future social instability.

A Machine Learning Approach to Identify Potential miRNA-Gene Regulatory Network Contributing to the Pathogenesis of SARS-CoV-2 Infection.

Worldwide, many lives have been lost in the recent outbreak of coronavirus disease. The pathogen responsible for this disease takes advantage of the host machinery to replicate itself and, in turn, causes pathogenesis in humans. Human miRNAs are seen to have a major role in the pathogenesis and progression of viral diseases. Hence, an in-silico approach has been used in this study to uncover the role of miRNAs and their target genes in coronavirus disease pathogenesis. This study attempts to perform the miRNA seq data analysis to identify the potential differentially expressed miRNAs. Considering only the experimentally proven interaction databases TarBase, miRTarBase, and miRecords, the target genes of the miRNAs have been identified from the mirNET analytics platform. The identified hub genes were subjected to gene ontology and pathway enrichment analysis using EnrichR. It is found that a total of 9 miRNAs are deregulated, out of which 2 were upregulated (hsa-mir-3614-5p and hsa-mir-3614-3p) and 7 were downregulated (hsa-mir-17-5p, hsa-mir-106a-5p, hsa-mir-17-3p, hsa-mir-181d-5p, hsa-mir-93-3p, hsa-mir-28-5p, and hsa-mir-100-5p). These miRNAs help us to classify the diseased and healthy control patients accurately. Moreover, it is also found that crucial target genes (UBC and UBB) of 4 signature miRNAs interact with viral replicase polyprotein 1ab of SARS-Coronavirus. As a result, it is noted that the virus hijacks key immune pathways like various cancer and virus infection pathways and molecular functions such as ubiquitin ligase binding and transcription corepressor and coregulator binding.

Integrative Bioinformatics-Gene Network Approach Reveals Linkage between Estrogenic Endocrine Disruptors and Vascular Remodeling in Peripheral Arterial Disease.

Vascular diseases, including peripheral arterial disease (PAD), pulmonary arterial hypertension, and atherosclerosis, significantly impact global health due to their intricate relationship with vascular remodeling. This process, characterized by structural alterations in resistance vessels, is a hallmark of heightened vascular resistance seen in these disorders. The influence of environmental estrogenic endocrine disruptors (EEDs) on the vasculature suggests a potential exacerbation of these alterations. Our study employs an integrative approach, combining data mining with bioinformatics, to unravel the interactions between EEDs and vascular remodeling genes in the context of PAD. We explore the molecular dynamics by which EED exposure may alter vascular function in PAD patients. The investigation highlights the profound effect of EEDs on pivotal genes such as ID3, LY6E, FOS, PTP4A1, NAMPT, GADD45A, PDGF-BB, and NFKB, all of which play significant roles in PAD pathophysiology. The insights gained from our study enhance the understanding of genomic alterations induced by EEDs in vascular remodeling processes. Such knowledge is invaluable for developing strategies to prevent and manage vascular diseases, potentially mitigating the impact of harmful environmental pollutants like EEDs on conditions such as PAD.

A Principal Components Analysis and Functional Annotation of Differentially Expressed Genes in Brain Regions of Gray Rats Selected for Tame or Aggressive Behavior.

The process of domestication, despite its short duration as it compared with the time scale of the natural evolutionary process, has caused rapid and substantial changes in the phenotype of domestic animal species. Nonetheless, the genetic mechanisms underlying these changes remain poorly understood. The present study deals with an analysis of the transcriptomes from four brain regions of gray rats (Rattus norvegicus), serving as an experimental model object of domestication. We compared gene expression profiles in the hypothalamus, hippocampus, periaqueductal gray matter, and the midbrain tegmental region between tame domesticated and aggressive gray rats and revealed subdivisions of differentially expressed genes by principal components analysis that explain the main part of differentially gene expression variance. Functional analysis (in the DAVID (Database for Annotation, Visualization and Integrated Discovery) Bioinformatics Resources database) of the differentially expressed genes allowed us to identify and describe the key biological processes that can participate in the formation of the different behavioral patterns seen in the two groups of gray rats. Using the STRING- DB (search tool for recurring instances of neighboring genes) web service, we built a gene association network. The genes engaged in broad network interactions have been identified. Our study offers data on the genes whose expression levels change in response to artificial selection for behavior during animal domestication.

Unraveling the link between atopic dermatitis and autoimmune diseases in children: Insights from a large-scale cohort study with 15-year follow-up and shared gene ontology analysis.

BACKGROUND: Atopic dermatitis and autoimmune diseases are highly heritable conditions that may co-occur from an early age. METHODS: The primary study is a national administrative cohort study involving 499,428 children born in 2002, tracked until 2017. Atopic dermatitis was defined as five or more principal diagnoses of atopic dermatitis and two or more topical steroid prescriptions. We estimated the risks for the occurrence of 41 autoimmune diseases, controlling for risk factors. In addition, we sourced a gene library from the National Library of Medicine to conduct a comprehensive gene ontology. We used Gene Weaver to identify gene set similarity and clustering, and used GeneMania to generate a network for shared genes. RESULTS: Exposed and unexposed groups included 39,832 and 159,328 children, respectively. During a mean follow-up of 12 years, the exposed group had an increased risk of autoimmune disease (hazard ratio, 1.27 [95 % confidence interval, 1.23-1.32]) compared to the unexposed group. The hazard ratios of autoimmune illnesses consistently increased with two- and five years lag times and alternative atopic dermatitis definitions. Shared genes between atopic dermatitis and autoimmune diseases were associated with comorbidities such as asthma, bronchiolitis, and specific infections. Genetic interactions of these shared genes revealed clustering in Th1, Th2, Th17, and non-classifiable pathways. CONCLUSIONS: Atopic dermatitis was significantly associated with an increased risk of subsequent autoimmune disease. we identified the genetically associated disease in atopic dermatitis patients comorbid with autoimmune disease and demonstrated a genetic network between atopic dermatitis and autoimmune diseases.

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Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the KISS1R and KISS1 genes and loss-of-function mutations in the MKRN3, LIN28, and DLK1 genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.

Priming-induced alterations in histone modifications modulate transcriptional responses in soybean under salt stress.

Plants that have experienced certain abiotic stress may gain tolerance to a similar stress in subsequent exposure. This phenomenon, called priming, was observed here in soybean (Glycine max) seedlings exposed to salt stress. Time-course transcriptomic profiles revealed distinctively different transcriptional responses in the primed seedlings from those in the non-primed seedlings under high salinity stress, indicating a stress response strategy of repressing unhelpful biotic stress responses and focusing on the promotion of those responses important for salt tolerance. To identify histone marks altered by the priming salinity treatment, a genome-wide profiling of histone 3 lysine 4 dimethylation (H3K4me2), H3K4me3, and histone 3 lysine 9 acetylation (H3K9ac) was performed. Our integrative analyses revealed that priming induced drastic alterations in these histone marks, which coordinately modified the stress response, ion homeostasis, and cell wall modification. Furthermore, transcriptional network analyses unveiled epigenetically modified networks which mediate the strategic downregulation of defense responses. Altering the histone acetylation status using a chemical inhibitor could elicit the priming-like transcriptional responses in non-primed seedlings, confirming the importance of histone marks in forming the priming response.

Constructing gene similarity networks using co-occurrence probabilities.

Gene similarity networks play important role in unraveling the intricate associations within diverse cancer types. Conventionally, gauging the similarity between genes has been approached through experimental methodologies involving chemical and molecular analyses, or through the lens of mathematical techniques. However, in our work, we have pioneered a distinctive mathematical framework, one rooted in the co-occurrence of attribute values and single point mutations, thereby establishing a novel approach for quantifying the dissimilarity or similarity among genes. Central to our approach is the recognition of mutations as key players in the evolutionary trajectory of cancer. Anchored in this understanding, our methodology hinges on the consideration of two categorical attributes: mutation type and nucleotide change. These attributes are pivotal, as they encapsulate the critical variations that can precipitate substantial changes in gene behavior and ultimately influence disease progression. Our study takes on the challenge of formulating similarity measures that are intrinsic to genes' categorical data. Taking into account the co-occurrence probability of attribute values within single point mutations, our innovative mathematical approach surpasses the boundaries of conventional methods. We thereby provide a robust and comprehensive means to assess gene similarity and take a significant step forward in refining the tools available for uncovering the subtle yet impactful associations within the complex realm of gene interactions in cancer.

The PAX-SIX-EYA-DACH network modulates GATA-FOG function in fly hematopoiesis and human erythropoiesis.

The GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) are essential for proper development across taxa. Here, we demonstrate novel PSEDN roles in vivo in Drosophila hematopoiesis and in human erythropoiesis in vitro Using Drosophila genetics, we show that PSEDN members function with GATA to block lamellocyte differentiation and maintain the prohemocyte pool. Overexpression of human SIX1 stimulated erythroid differentiation of human erythroleukemia TF1 cells and primary hematopoietic stem-progenitor cells. Conversely, SIX1 knockout impaired erythropoiesis in both cell types. SIX1 stimulation of erythropoiesis required GATA1, as SIX1 overexpression failed to drive erythroid phenotypes and gene expression patterns in GATA1 knockout cells. SIX1 can associate with GATA1 and stimulate GATA1-mediated gene transcription, suggesting that SIX1-GATA1 physical interactions contribute to the observed functional interactions. In addition, both fly and human SIX proteins regulated GATA protein levels. Collectively, our findings demonstrate that SIX proteins enhance GATA function at multiple levels, and reveal evolutionarily conserved cooperation between the GATA and PSEDN networks that may regulate developmental processes beyond hematopoiesis.