Dorsal Striatum Transcriptome Profile Profound Shift in Repeated Aggression Mouse Model Converged to Networks of 12 Transcription Factors after Fighting Deprivation

Both aggressive and aggression-deprived (AD) species represent pathologic cases intensely addressed in psychiatry and substance abuse disciplines. Previously, we reported that AD mice displayed a higher aggressive behavior score than the aggressive group, implying the manifestation of a withdrawal effect. We employed an animal model of chronic social conflicts, curated in our lab for more than 30 years. In the study, we pursued the task of evaluating key events in the dorsal striatum transcriptome of aggression experienced mice and AD species compared to controls using RNA-Seq profiling. Aggressive species were subjected to repeated social conflict encounters (fights) with regular positive (winners) experience in the course of 20 consecutive days (A20 group). This led to a profoundly shifted transcriptome expression profile relative to the control group, outlined by more than 1000 differentially expressed genes (DEGs). RNA-Seq cluster analysis revealed that elevated cyclic AMP (cAMP) signaling cascade and associated genes comprising 170 differentially expressed genes (DEGs) in aggressive (A20) species were accompanied by a downturn in the majority of other metabolic/signaling gene networks (839 DEGs) via the activation of transcriptional repressor DEGs. Fourteen days of a consecutive fighting deprivation period (AD group) featured the basic restoration of the normal (control) transcriptome expression profile yielding only 62 DEGs against the control. Notably, we observed a network of 12 coordinated DEG Transcription Factor (TF) activators from 62 DEGs in total that were distinctly altered in AD compared to control group, underlining the distinct transcription programs featuring AD group, partly retained from the aggressive encounters and not restored to normal in 14 days. We found circadian clock TFs among them, reported previously as a withdrawal effect factor. We conclude that the aggressive phenotype selection with positive reward effect (winning) manifests an addiction model featuring a distinct opioid-related withdrawal effect in AD group. Along with reporting profound transcriptome alteration in A20 group and gaining some insight on its specifics, we outline specific TF activator gene networks associated with transcriptional repression in affected species compared to controls, outlining Nr1d1 as a primary candidate, thus offering putative therapeutic targets in opioid-induced withdrawal treatment.

Network Analysis of Different Exogenous Hormones on the Regulation of Deep Sowing Tolerance in Maize Seedlings

The planting method of deep sowing can make the seeds make full use of water in deep soil, which is considered to be an effective way to respond to drought stress. However, deep sowing will affect the growth and development of maize (Zea mays L.) at seedling stage. To better understand the response of maize to deep sowing stress and the mechanism of exogenous hormones [Gibberellin (GA3), Brassinolide (BR), Strigolactone (SL)] alleviates the damaging effects of deep-sowing stress, the physiological and transcriptome expression profiles of seedlings of deep sowing sensitive inbred line Zi330 and the deep-tolerant inbred line Qi319 were compared under deep sowing stress and the conditions of exogenous hormones alleviates stress. The results showed that mesocotyl elongated significantly after both deep sowing stress and application of exogenous hormones, and its elongation was mainly through elongation and expansion of cell volume. Hormone assays revealed no significant changes in zeatin (ZT) content of the mesocotyl after deep sowing and exogenous hormone application. The endogenous GA3 and auxin (IAA) contents in the mesocotyl of the two inbred lines increased significantly after the addition of exogenous GA3, BR, and SL under deep sowing stress compared to deep sowing stress, while BR and SL decreased significantly. Transcriptome analysis showed that the deep seeding stress was alleviated by GA3, BR, and SLs, the differentially expressed genes (DEGs) mainly included cellulose synthase, expansin and glucanase, oxidase, lignin biosynthesis genes and so on. We also found that protein phosphatase 2C and GA receptor GID1 enhanced the ability of resist deep seeding stress in maize by participating in the abscisic acid (ABA) and the GA signaling pathway, respectively. In addition, we identified two gene modules that were significantly related to mesocotyl elongation, and identified some hub genes that were significantly related to mesocotyl elongation by WGCNA analysis. These genes were mainly involved in transcription regulation, hydrolase activity, protein binding and plasma membrane. Our results from this study may provide theoretical basis for determining the maize deep seeding tolerance and the mechanism by which exogenous hormones regulates deep seeding tolerance.

Genome-wide expression of the residual lung reacting to experimental Pneumonectomy

Background Acute or chronic irreversible respiratory failure may occur in patients undergoing pneumonectomy. Aim of this study was to determine transcriptome expression changes after experimental pneumonectomy in swine model. Experimental left pneumonectomy was performed in five pigs under general anaesthesia. Both the resected and the remaining lung, after 60 post-operative completely uneventful days, underwent genome-wide bulk RNA-Sequencing (RNA-Seq). Results Histological analysis showed dilation of air spaces and rupture of interalveolar septa. In addition, mild inflammation, no fibrosis, radial stretch of the bronchus, strong enlargement of airspaces and thinning of the blood supply were observed. Bioinformatic analyses of bulk RNA-Seq data identified 553 Differentially Expressed Genes (DEGs) at adjusted P-value below 0.001, between pre- and post-pneumonectomy. The top 10 up-regulated DEGs were Edn1, Areg, Havcr2, Gadd45g, Depp1, Cldn4, Atf3, Myc, Gadd45b, Socs3; the top 10 down-regulated DEGs were Obscn, Cdkn2b, ENSSSCG00000015738, Prrt2, Amer1, Flrt3, Efnb2, Tox3, Znf793, Znf365. Leveraging digital cytometry tools, no difference in cellular abundance was found between the two experimental groups, while the analysis of cell type-specific gene expression patterns highlighted a striking predominance of macrophage-specific genes among the DEGs. DAVID-based gene ontology analysis showed a significant enrichment of “Extrinsic apoptotic signaling pathway” (FDR q = 7.60 × 10− 3) and “Response to insulin” (FDR q = 7.60 × 10− 3) genes, along with an enrichment of genes involved as “Negative regulators of DDX58/IFIH1 signaling” (FDR q = 7.50 × 10− 4) found by querying the REACTOME pathway database. Gene network analyses indicated a general dysregulation of gene inter-connections. Conclusion This translational genomics study highlighted the existence both of individual genes, mostly dysregulated in certain cellular populations (e.g., macrophages), and gene-networks involved in pulmonary reaction after left pneumonectomy. Their involvement in lung homeostasis is largely supported by previous studies, carried out both in humans and in other animal models (under homeostatic or disease-related conditions), that adopted candidate-gene approaches. Overall, the present findings represent a preliminary assessment for future, more focused, studies on compensatory lung adaptation, pulmonary regeneration and functional reload.

The effects of introgression across thousands of quantitative traits revealed by gene expression in wild tomatoes

It is now understood that introgression can serve as powerful evolutionary force, providing genetic variation that can shape the course of trait evolution. Introgression also induces a shared evolutionary history that is not captured by the species phylogeny, potentially complicating evolutionary analyses that use a species tree. Such analyses are often carried out on gene expression data across species, where the measurement of thousands of trait values allows for powerful inferences while controlling for shared phylogeny. Here, we present a Brownian motion model for quantitative trait evolution under the multispecies network coalescent framework, demonstrating that introgression can generate apparently convergent patterns of evolution when averaged across thousands of quantitative traits. We test our theoretical predictions using whole-transcriptome expression data from ovules in the wild tomato genus Solanum. Examining two sub-clades that both have evidence for post-speciation introgression, but that differ substantially in its magnitude, we find patterns of evolution that are consistent with histories of introgression in both the sign and magnitude of ovule gene expression. Additionally, in the sub-clade with a higher rate of introgression, we observe a correlation between local gene tree topology and expression similarity, implicating a role for introgressed cis-regulatory variation in generating these broad-scale patterns. Our results reveal a general role for introgression in shaping patterns of variation across many thousands of quantitative traits, and provide a framework for testing for these effects using simple model-informed predictions.

Agent Clustering Strategy Based on Metabolic Flux Distribution and Transcriptome Expression for Novel Drug Development

The network module-based method has been used for drug repositioning. The traditional drug repositioning method only uses the gene characteristics of the drug but ignores the drug-triggered metabolic changes. The metabolic network systematically characterizes the connection between genes, proteins, and metabolic reactions. The differential metabolic flux distribution, as drug metabolism characteristics, was employed to cluster the agents with similar MoAs (mechanism of action). In this study, agents with the same pharmacology were clustered into one group, and a total of 1309 agents from the CMap database were clustered into 98 groups based on differential metabolic flux distribution. Transcription factor (TF) enrichment analysis revealed the agents in the same group (such as group 7 and group 26) were confirmed to have similar MoAs. Through this agent clustering strategy, the candidate drugs which can inhibit (Japanese encephalitis virus) JEV infection were identified. This study provides new insights into drug repositioning and their MoAs.

CBIO-10. TARGETING HISTONE H4 Lys 20 MONOMETHYLATION IN THE TREATMENT OF GLIOBLASTOMA

BACKGROUND Glioblastoma (GBM) is the most malignant primary tumor of the central nervous system, while the pathogenesis remains unclear. Protein lysine methyltransferase SETD8, which is responsible for the modification of histone H4K20me1, has been shown to play an important role in cellular transcriptional regulation and the development of a variety of tumors, yet its role in the malignant progression of GBM has not been elucidated. MATERIAL AND METHODS In the present study, we used primary GBM cell lines, intracranial xenograft model, transcriptome sequencing together with ChIP-sequencing, aiming to elucidate the molecular mechanism of SETD8-mediated H4K20me1 transcriptional regulation in promoting GBM progression. Furthermore, we evaluated the potential therapeutic significance in GBM using SETD8 small molecule inhibitor, UNC0379. RESULTS We found that SETD8 is aberrantly expressed in GBM tissues, accompanied by the dysregulation of H4K20me1 modification, which is associated with tumor pathology and prognosis. Using SETD8 inhibitor UNC0379 or knockdown of SETD8 significantly inhibited GBM cell proliferation in vitro and in vivo, and downregulated H4K20me1 modification level as well as transcriptome expression. CONCLUSION In summary, our work provide a novel insight into the role of SETD8/H4K20me1 axis. SETD8 overexpression mediated aberrant H4K20me1 modification act as a novel "transcriptional switch" in the malignant progression of glioma.

Transcriptome profiles of the skeletal muscle of mature cows during feed restriction and realimentation

Objective Realimentation can compensate for weight loss from poor-quality feedstuffs or drought. Mature cows fluctuate in body weight throughout the year due to nutrient availability. The objective of this study was to determine whether cows that differ in weight gain during realimentation also differ in the abundance of transcripts for enzymes associated with energy utilization in skeletal muscle. Mature cows were subjected to feed restriction followed by ad libitum feed. Skeletal muscle transcriptome expression differences during the two feeding periods were determined from cows with greater (n = 6) and less (n = 6) weight gain during the ad libitum feeding period. Results A total of 567 differentially expressed genes (408 up- and 159 down-regulated) were identified for the comparison of restriction and ad libitum periods (PBonferroni < 0.05). These genes were over-represented in lysosome, aminoacyl-tRNA biosynthesis, and glutathione metabolism pathways. Validation of the expression of five of the genes was performed and four were confirmed. These data suggest that realimentation weight gain for all cows is partially controlled by protein turnover, but oxidative stress and cellular signaling pathways are also involved in the muscle tissue. This dataset provides insight into molecular mechanisms utilized by mature cows during realimentation after a period of low abundance feed.

Transcriptomic Signatures of Airway Epithelium Infected With SARS-CoV-2: A Balance Between Anti-infection and Virus Load

COVID-19 pneumonia requires effective medical therapies. However, it is a challenge to find therapeutic drugs that not only inhibit viral replication, but also inhibit the accompanying cytokine storm and maintain an appropriate immune response. In this study, the effects of SARS-CoV-2 on gene expression in lung epithelial cells from patients with COVID-19 were systematically evaluated with bioinformatics analysis methods. Transcriptome expression specific to bystander (exposed but uninfected) and infected cells were found, and the vital pathways were identified by conducting differentially expressed gene analysis regarding the relationship between gene signatures of COVID-19 infection and disease severity. We found that a high viral load did not necessarily imply a low response of epithelial cells or a poor disease convalescence. The ability to distinguish the role of virus-correlated genes facilitates the development of potential new medicines and therapies for COVID-19 infection.

Conservative and Atypical Ferritins of Sponges

Ferritins comprise a conservative family of proteins found in all species and play an essential role in resistance to redox stress, immune response, and cell differentiation. Sponges (Porifera) are the oldest Metazoa that show unique plasticity and regenerative potential. Here, we characterize the ferritins of two cold-water sponges using proteomics, spectral microscopy, and bioinformatic analysis. The recently duplicated conservative HdF1a/b and atypical HdF2 genes were found in the Halisarca dujardini genome. Multiple related transcripts of HpF1 were identified in the Halichondria panicea transcriptome. Expression of HdF1a/b was much higher than that of HdF2 in all annual seasons and regulated differently during the sponge dissociation/reaggregation. The presence of the MRE and HRE motifs in the HdF1 and HdF2 promotor regions and the IRE motif in mRNAs of HdF1 and HpF indicates that sponge ferritins expression depends on the cellular iron and oxygen levels. The gel electrophoresis combined with specific staining and mass spectrometry confirmed the presence of ferric ions and ferritins in multi-subunit complexes. The 3D modeling predicts the iron-binding capacity of HdF1 and HpF1 at the ferroxidase center and the absence of iron-binding in atypical HdF2. Interestingly, atypical ferritins lacking iron-binding capacity were found in genomes of many invertebrate species. Their function deserves further research.