Regulation Of Gene Expression Levels Research Articles

Exploratory Analysis of MicroRNA Alterations in a Neurodevelopmental Mouse Model for Autism Spectrum Disorder and Schizophrenia.

MicroRNAs (miRNAs) play a crucial role in the regulation of gene expression levels and have been implicated in the pathogenesis of autism spectrum disorder (ASD) and schizophrenia (SCZ). In this study, we examined the adult expression profiles of specific miRNAs in the prefrontal cortex (PFC) of a neurodevelopmental mouse model for ASD and SCZ that mimics perinatal pathology, such as NMDA receptor hypofunction, and exhibits behavioral and neurophysiological phenotypes related to these disorders during adulthood. To model the early neuropathogenesis of the disorders, mouse pups were administered subcutaneously with ketamine (30 mg/Kg) at postnatal days 7, 9, and 11. We focused on a set of miRNAs most frequently altered in ASD (miR-451a and miR-486-3p) and in SCZ (miR-132-3p and miR-137-3p) according to human studies. Additionally, we explored miRNAs whose alterations have been identified in both disorders (miR-21-5p, miR-92a-2-5p, miR-144-3p, and miR-146a-5p). We placed particular emphasis on studying the sexual dimorphism in the dynamics of these miRNAs. Our findings revealed significant alterations in the PFC of this ASD- and SCZ-like mouse model. Specifically, we observed upregulated miR-451a and downregulated miR-137-3p. Furthermore, we identified sexual dimorphism in the expression of miR-132-3p, miR-137-3p, and miR-92a-2-5p. From a translational perspective, our results emphasize the potential involvement of miR-92a-2-5p, miR-132-3p, miR-137-3p, and miR-451a in the pathophysiology of ASD and SCZ and strengthen their potential as biomarkers and therapeutic targets of such disorders.

Transcriptome analysis reveals important regulatory factors for condensed tannins synthesis in acorn.

Condensed tannins are widely present in the fruits and seeds of plants and effectively prevent them from being eaten by animals before maturity due to their astringent taste. In addition, condensed tannins are a natural compound with strong antioxidant properties and significant antibacterial effects. Four samples of mature and near-mature Quercus fabri acorns, with the highest and lowest condensed tannin content, were used for genome-based transcriptome sequencing. The KEGG enrichment analysis revealed that the differentially expressed genes (DEGs) were highly enriched in phenylpropanoid biosynthesis and starch and sucrose metabolism. Given that the phenylpropanoid biosynthesis pathway is a crucial step in the synthesis of condensed tannins, we screened for significantly differentially expressed transcription factors and structural genes from the transcriptome data of this pathway and found that the expression levels of four MADS-box, PAL, and 4CL genes were significantly increased in acorns with high condensed tannin content. The quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) experiment further validated this result. In addition, yeast one-hybrid assay confirmed that three MADS-box transcription factors could bind the promoter of the 4CL gene, thereby regulating gene expression levels. This study utilized transcriptome sequencing to discover new important regulatory factors that can regulate the synthesis of acorn condensed tannins, providing new evidence for MADS-box transcription factors to regulate the synthesis of secondary metabolites in fruits.

The Functions of N6-Methyladenosine in Nuclear RNAs.

N6-methyladenosine (m6A) is one of the most common modifications in both eukaryotic and prokaryotic mRNAs. It has been experimentally confirmed that m6A methylation is involved in the regulation of stability and translation of various mRNAs. Until recently, the majority of m6A-related studies have been focused on the cytoplasmic functions of this modification. Here, we review new data on the role of m6A in several key biological processes taking place in the cell nucleus, such as transcription, chromatin organization, splicing, nuclear-cytoplasmic transport, and R-loop metabolism. Based on analysis of these data, we suggest that m6A methylation of nuclear RNAs is another level of gene expression regulation which, together with DNA methylation and histone modifications, controls chromatin structure and functioning in various biological contexts.

A Review of Advanced Cutaneous Melanoma Therapies and Their Mechanisms, from Immunotherapies to Lysine Histone Methyl Transferase Inhibitors.

Advanced cutaneous melanoma is considered to be the most aggressive type of skin cancer and has variable rates of treatment response. Currently, there are some classes of immunotherapy and target therapies for its treatment. Immunotherapy can inhibit tumor growth and its recurrence by triggering the host's immune system, whereas targeted therapy inhibits specific molecules or signaling pathways. However, melanoma responses to these treatments are highly heterogeneous, and patients can develop resistance. Epigenomics (DNA/histone modifications) contribute to cancer initiation and progression. Epigenetic alterations are divided into four levels of gene expression regulation: DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation. Deregulation of lysine methyltransferase enzymes is associated with tumor initiation, invasion, development of metastases, changes in the immune microenvironment, and drug resistance. The study of lysine histone methyltransferase (KMT) and nicotinamide N-methyltransferase (NNMT) inhibitors is important for understanding cancer epigenetic mechanisms and biological processes. In addition to immunotherapy and target therapy, the research and development of KMT and NNMT inhibitors is ongoing. Many studies are exploring the therapeutic implications and possible side effects of these compounds, in addition to their adjuvant potential to the approved current therapies. Importantly, as with any drug development, safety, efficacy, and specificity are crucial considerations when developing methyltransferase inhibitors for clinical applications. Thus, this review article presents the recently available therapies and those in development for advanced cutaneous melanoma therapy.

The streptococcal phase-variable type I restriction modification system SsuCC20p dictates the methylome of Streptococcus suis impacting the transcriptome and virulence in a zebrafish larvae infection model.

Phase variation allows a single strain to produce phenotypic diverse subpopulations. Phase-variable restriction modification (RM) systems are systems that allow for such phase variation via epigenetic regulation of gene expression levels. The phase-variable RM system SsuCC20p was found in multiple streptococcal species and was acquired by an emerging zoonotic lineage of Streptococcus suis. We show that the phase variability of SsuCC20p is dependent on a recombinase encoded within the SsuCC20p locus. We characterized the genome methylation profiles of the different phases of SsuCC20p and demonstrated the consequential impact on the transcriptome and virulence in a zebrafish infection model. Acquiring mobile genetic elements containing epigenetic regulatory systems, like phase-variable RM systems, enables bacterial pathogens to produce diverse phenotypic subpopulations that are better adapted to specific (host) environments encountered during infection.

Prediction of circRNA-MiRNA Association Using Singular Value Decomposition and Graph Neural Networks.

A large number of experimental studies have shown that circRNAs can act as molecular sponges of microRNAs, interacting with miRNAs to regulate gene expression levels, thereby affecting the development of human diseases. Exploring the potential associations between circRNAs and miRNAs can help understand complex disease mechanisms. Considering that biological experiments are time-consuming and labor-intensive, this study proposes a computational model using a graph neural network and singular value decomposition (CMASG) for circRNA-miRNA association prediction. Specifically, graph neural networks are used to learn nonlinear feature representations of nodes, followed by matrix factorization algorithms to learn linear feature representations of nodes, and then combined feature representations learned from different perspectives. Finally, the lightGBM algorithm was used for circRNA-miRNA association prediction. The proposed CMASG model achieved an AUC value of 0.8804. The experimental results demonstrate the superiority and effectiveness of the CMASG model in predicting circRNA-miRNA association tasks.

Running from stress: a perspective on the potential benefits of exercise-induced small extracellular vesicles for individuals with major depressive disorder.

Aerobic exercise promotes beneficial effects in the brain including increased synaptic plasticity and neurogenesis and regulates neuroinflammation and stress response via the hypothalamic-pituitary-adrenal axis. Exercise can have therapeutic effects for numerous brain-related pathologies, including major depressive disorder (MDD). Beneficial effects of aerobic exercise are thought to be mediated through the release of "exerkines" including metabolites, proteins, nucleic acids, and hormones that communicate between the brain and periphery. While the specific mechanisms underlying the positive effects of aerobic exercise on MDD have not been fully elucidated, the evidence suggests that exercise may exert a direct or indirect influence on the brain via small extracellular vesicles which have been shown to transport signaling molecules including "exerkines" between cells and across the blood-brain barrier (BBB). sEVs are released by most cell types, found in numerous biofluids, and capable of crossing the BBB. sEVs have been associated with numerous brain-related functions including neuronal stress response, cell-cell communication, as well as those affected by exercise like synaptic plasticity and neurogenesis. In addition to known exerkines, they are loaded with other modulatory cargo such as microRNA (miRNA), an epigenetic regulator that regulates gene expression levels. How exercise-induced sEVs mediate exercise dependent improvements in MDD is unknown. Here, we perform a thorough survey of the current literature to elucidate the potential role of sEVs in the context of neurobiological changes seen with exercise and depression by summarizing studies on exercise and MDD, exercise and sEVs, and finally, sEVs as they relate to MDD. Moreover, we describe the links between peripheral sEV levels and their potential for infiltration into the brain. While literature suggests that aerobic exercise is protective against the development of mood disorders, there remains a scarcity of data on the therapeutic effects of exercise. Recent studies have shown that aerobic exercise does not appear to influence sEV size, but rather influence their concentration and cargo. These molecules have been independently implicated in numerous neuropsychiatric disorders. Taken together, these studies suggest that concentration of sEVs are increased post exercise, and they may contain specifically packaged protective cargo representing a novel therapeutic for MDD.

Deacetylation of Histones and Non-histone Proteins in Inflammatory Diseases and Cancer Therapeutic Potential of Histone Deacetylase Inhibitors.

Epigenetic changes play an important role in the pathophysiology of autoimmune diseases such as allergic asthma, multiple sclerosis, lung diseases, diabetes, cystic fibrosis, atherosclerosis, rheumatoid arthritis, and COVID-19. There are three main classes of epigenetic alterations: post-translational modifications of histone proteins, control by non-coding RNA and DNA methylation. Since histone modifications can directly affect chromatin structure and accessibility, they can regulate gene expression levels. Abnormal expression and activity of histone deacetylases (HDACs) have been reported in immune mediated diseases. Increased acetylated levels of lysine residues have been suggested to be related to the overexpression of inflammatory genes. This review focuses on the effect of HDAC modifications on histone and non-histone proteins in autoimmune diseases. Furthermore, we discuss the potential therapeutic effect of HDAC inhibitors (HDACi) used in these diseases.

Cytotoxic Effect of Prunus Divaricata Ledeb. Extract on Lung Cancer Cells and Determination of Expression Profiles of Genes in the MAP-Kinase Pathway

Cherry plum (Prunus divaricata Ledeb.) is a diploid fruit tree that belongs to the Rosaceae family. Anticarcinogenic activity of Prunus divaricata Ledeb. methanol extract was examined in lung cancer cell lines A549 and H1299 as well as in healthy cell line Beas-2b in this study. The changes in the expression levels of the most frequently mutated oncogenes in lung cancer, KRAS, EGFR, BRAF, and PIK3CA were investigated as well. In vitro cytotoxicity assays of P. divaricata Ledeb. fruit methanol extract was conducted by measuring the percentage of viable cells spectrophotometrically using the cell viability identification kit (CVDK) based on the colorimetric method. The AB 7500 Fast RT-PCR device with Sybr Green Master Mix was used to create gene expression profiles, and the Ct values of all genes were assessed by normalizing the Ct value of the housekeeping gene. The methanol extract of P. divaricata Ledeb. fruit was found to have a cytotoxic effect on A549 and H1299 cancer cell lines at 20 mg/ml, but not on the Beas-2b cell line at these concentrations. By reducing proliferation, low KRAS and PIK3CA gene expression caused the cells to undergo apoptosis. The methanol extract of P. divaricata Ledeb. fruit has been found to inhibit the development of cancerous cells while promoting the proliferation of healthy cells. We believe it does this through the apoptotic pathway by regulating gene expression levels in oncogenes via the MAP-Kinase pathway.

Noncoding RNA Regulation of Hormonal and Metabolic Systems in the Fruit Fly Drosophila

The importance of RNAs is commonly recognised thanks to protein-coding RNAs, whereas non-coding RNAs (ncRNAs) were conventionally regarded as 'junk'. In the last decade, ncRNAs' significance and roles are becoming noticeable in various biological activities, including those in hormonal and metabolic regulation. Among the ncRNAs: microRNA (miRNA) is a small RNA transcript with ~20 nucleotides in length; long non-coding RNA (lncRNA) is an RNA transcript with >200 nucleotides; and circular RNA (circRNA) is derived from back-splicing of pre-mRNA. These ncRNAs can regulate gene expression levels at epigenetic, transcriptional, and post-transcriptional levels through various mechanisms in insects. A better understanding of these crucial regulators is essential to both basic and applied entomology. In this review, we intend to summarise and discuss the current understanding and knowledge of miRNA, lncRNA, and circRNA in the best-studied insect model, the fruit fly Drosophila.

Research advances on the structure, function and regulation of NIP aquaporins in plants

<p indent="0mm">Aquaporin protein (AQP) family, as a “carrier” of water, micronutrients, and solute macromolecules in plants, plays an important role in material transport. Unlike other members of the AQP family, nodulin 26-like intrinsic proteins (NIPs) mainly penetrate small molecules, such as water, glycerin, silicic acid, boric acid, and urea. In addition, it is involved in plant cell osmoregulation, seed germination, lateral root production, leaf and flower growth and development, and response to biotic and abiotic (drought, chilling, salinity, metalloid toxicity, hypoxia, etc.) stresses. So far, structures of the NIP family have been partially reported. The NIPs can be divided into three classes based on the pore size of the ar/R selective filter, which determines the absorption and transportation of different substrates. Moreover, the NIPs contain two NPA motifs, which are located in loop B and loop E and have a typical ring-like hourglass structure. Therefore, different structures of the NIP subfamily play different roles in plant membrane solute transport and water balance. The <italic>NIP</italic> gene family has been identified in <italic>Arabidopsis thaliana</italic>,<italic> Oryza sativa</italic>, and other plants, whose function needs to be achieved through a variety of signaling pathways and the synergistic effect of physiological processes. In recent years, more and more reports have shown how the <italic>NIP</italic> gene participates in regulating gene expression levels under various stress conditions and interacts with a variety of stress proteins to jointly regulate the water and osmotic balance of plants and improve plant resistance and adaptability. The co-expression of <italic>NIPs</italic> with <italic>AtBOR1</italic>, <italic>AtNodGS</italic>, and <italic>AtACR3</italic> genes can enhance the transport of solute and aquaporin. Besides, the interaction between NIP and 14-3-3f proteins can stabilize cell structure and substance synthesis in vivo, thus enhancing plant cold resistance. Interestingly, <italic>NIP</italic> is regulated by WRKY transcription factors and plays an active role in the regulation and distribution of metalloid elements in plants. In addition, the <italic>NIP </italic>genes are involved in the response of various hormone signaling pathways in plants, and their gating mechanisms and osmotic stress responses are regulated by the C- and N-terminal phosphorylation sites of NIP proteins, but the specific response mechanisms remain to be further explored. <italic>NIPs</italic> are a large multi-gene family with functional redundancy among members, and the similarities and differences in functions and mechanisms of different subfamilies of <italic>NIP</italic> genes need to be investigated. One of our main subsequent research directions is to explore the stress resistance network of the <italic>NIP</italic> genes, especially their response mechanisms to biotic stress. What’s more, NIPs can interact with PIP proteins belonging to the AQP family and affect the diffusion of water molecules by changing their positions. Therefore, whether NIPs interact with other members of the AQP family, such as SIPs and TIPs, deserves to be validated further. In summary, the origin and evolution, structure, classification, biological function, and regulation mechanism of the NIP family in plants are reviewed, which provides new insights and references for further research.

Comparative Analysis of Alternative Splicing in Two Contrasting Apple Cultivars Defense against Alternaria alternata Apple Pathotype Infection.

Alternaria blotch disease, caused by the Alternaria alternata apple pathotype (A. alternata AP), is one of the most serious fungal diseases in apples. Alternative splicing (AS), one of the pivotal post-transcriptional regulatory mechanisms, plays essential roles in various disease resistance responses. Here, we performed RNA-Seq for two apple cultivars (resistant cultivar 'Jonathan' (J) and susceptible cultivar 'Starking Delicious' (SD)) infected by A. alternata AP to further investigate their AS divergence. In total, 1454, 1780, 1367 and 1698 specifically regulated differential alternative splicing (DAS) events were detected in J36, J72, SD36 and SD72 groups, respectively. Retained intron (RI) was the dominant AS pattern. Conformably, 642, 764, 585 and 742 uniquely regulated differentially spliced genes (DSGs) were found during A. alternata AP infection. Comparative analysis of AS genes in differential splicing and expression levels suggested that only a small proportion of DSGs overlapped with differentially expressed genes (DEGs). Gene ontology (GO) enrichment analysis demonstrated that the DSGs were significantly enriched at multiple levels of gene expression regulation. Briefly, the specific AS was triggered in apple defense against A. alternata AP. Therefore, this study facilitates our understanding on the roles of AS regulation in response to A. alternata AP infection in apples.

SLU7: A New Hub of Gene Expression Regulation-From Epigenetics to Protein Stability in Health and Disease.

SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.

Regulatory RNAs in the molecular pathology of neoplasia

<p indent="0mm">Deregulation of gene expression is the fundamental basis of tumorigenesis and tumor progression. Regulatory RNAs play important roles at multiple levels of gene expression regulation and in various cell biological processes. Major progress has been made in molecular biological research of neoplasia regarding biogenesis, biological functions, roles, and molecular mechanisms of various regulatory RNAs, including microRNA, circular RNA, long noncoding RNA, piRNA, snoRNA, and tsRNA. The results of basic research have been gradually translated into clinical applications. Herein, we review the essential progress in the research on regulatory RNAs in the molecular biology of tumors.

Circ_0051079 functions as an oncogenic regulator in osteosarcoma by leading to MAFB expression upregulation by competitively interacting with miR-1286

BackgroundCircular RNAs are involved in various cellular processes of bone diseases by acting as miRNA sponges to regulate gene expression levels, including osteosarcoma (OS). This research concentrated on the molecular mechanism of circ_0051079 in OS progression.MethodsReverse transcription-quantitative polymerase chain reaction assay was used for expression detection of circ_0051079, microRNA-1286 (miR-1286), and musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB). Cell Counting Kit-8 assay and Edu assay were used for cell proliferation analysis. Cell apoptosis was evaluated using flow cytometry. Western blot was performed to measure protein levels. Migration and invasion were assessed via transwell assay. Interaction of circ_0051079/miR-1286 or miR-1286/MAFB was explored through a dual-luciferase reporter assay. In vivo research was carried out via tumor xenograft assay and immunohistochemistry staining.ResultsCirc_0051079 expression was upregulated in OS. Downregulation of circ_0051079 reduced OS cell proliferation, migration, invasion, and accelerated apoptosis. Circ_0051079 interacted with miR-1286, and the tumor-inhibitory function of si-circ_0051079 was abolished by miR-1286 inhibition in OS cells. MAFB served as a target for miR-1286. OS cell progression was suppressed by miR-1286 overexpression via downregulating MAFB. Circ_0051079/miR-1286 resulted in expression change of MAFB in OS cells. Silencing circ_0051079 inhibited tumor growth in vivo via regulating the miR-1286/MAFB axis.ConclusionThe collective results elucidated that circ_0051079 contributed to OS progression via miR-1286-mediated upregulation of MAFB, confirming the interaction of circ_0051079/miR-1286/MAFB axis in OS.

Regulation Networks of Non-Coding RNA-Associated ceRNAs in Cisplatin-Induced Acute Kidney Injury.

Cisplatin is widely used as a chemotherapeutic drug to treat various solid tumors. However, it often induces severe side effects, including nephrotoxicity, which limits its application in clinical settings. Furthermore, the underlying mechanisms of action are unclear. Here, we applied whole-transcriptome RNA sequencing to a cisplatin-induced acute kidney injury (CP-AKI) mouse model to evaluate competing endogenous RNA (ceRNA) networks. We found 4460 mRNAs, 1851 long non-coding RNAs, 101 circular RNAs, and 102 microRNAs significantly differentially expressed between CP-AKI and control mice. We performed gene set enrichment analysis to reveal the biological functions of the mRNAs and constructed non-coding RNA-associated ceRNA networks in CP-AKI mice. Two ceRNA regulatory pathways, Lhx1os-203/mmu-miR-21a-3p/Slc7a13 and circular RNA_3907/mmu-miR-185-3p/Ptprn, were validated using quantitative real-time PCR. The protein–protein interaction network indicated that Il6, Cxcl1, Cxcl2, and Plk1 serve as hub genes and are highly connected with the inflammatory response or DNA damage. Transcription factors, such as Stat3, Cebpb, and Foxm1, regulate gene expression levels in CP-AKI. Our study provides insight into non-coding RNA-associated ceRNA networks and mRNAs in CP-AKI and identifies potential treatment targets.

A Universal Method for Developing Autoinduction Expression Systems Using AHL-Mediated Quorum-Sensing Circuits.

A major challenge in engineering microorganisms for the desirable product is maintaining the rational balance between cell growth and production. Quorum sensing (QS)-based dynamic regulations provide a pathway-independent genetic control technology to rebalance metabolic flux for biomass and product synthesis. However, the lack of a universal method for screening QS elements and the complex design of autoinduction circuits limit their applications in metabolic engineering. Here, we developed a universal method for simple and rapid screening and evaluating various QS systems from Gram-negative bacteria, and the largest library containing 195 combinations of receiving device/signal molecules was constructed and evaluated in Escherichia coli. A simple logical circuit with different inducer synthesis rates was established to dynamically regulate gene expression levels, leading to efficient protein expression and product synthesis. The system was further applied in Pseudomonas putida, which indicated it could be widely accommodated in other microorganisms. Therefore, the method could be used in diverse Gram-negative strains for the desired biosynthesis.

Identification of circular RNA biomarkers for Pien Tze Huang treatment of CCl4‑induced liver fibrosis using RNA‑sequencing

Pien Tze Huang (PZH), a common hepatoprotective Traditional Chinese Medicine that has been found to be an effective treatment for carbon tetrachloride-induced hepatic damage, including liver fibrosis. Circular RNAs (circRNAs) serve a crucial role in regulating gene expression levels via circRNA/micro (mi)RNA/mRNA networks in several human diseases and biological processes. However, whether circRNAs are involved in the underlying mechanism of the therapeutic effects of PZH on liver fibrosis remains unclear. Therefore, the aim of the present study was to investigate these effects using circRNA expression profiles from PZH-treated fibrotic livers in model mice. A case-control study on >59,476 circRNAs from CCl4-induced (control group, n=6) and PZH-treated (case group, n=6) mice was performed using circRNA sequencing in liver tissues. PZH treatment resulted in the differential expression of 91 circRNAs, including 58 upregulated and 33 downregulated circRNAs. Furthermore, the construction of competing endogenous networks also indicated that differentially expressed circRNAs acted as miRNA sponges. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of miRNA targets demonstrated that PZH-affected circRNAs were mainly involved in biological processes such as ‘positive regulation of fibroblast proliferation’, ‘cellular response to interleukin-1’ and ‘regulation of DNA-templated transcription in response to stress’ and in a number of important pathways, such as ‘TNF signaling pathway’, ‘PI3K-Akt signaling pathway’, ‘IL-17 signaling pathway’ and ‘MAPK signaling pathway’. To further validate the bioinformatics data, reverse transcription–quantitative PCR was performed on seven miRNA targets in a human hepatic stellate LX-2 cell model. The results suggested that seven of the miRNAs exhibited regulatory patterns that were consistent with those of the transcriptome sequencing results. Kaplan-Meier survival analysis demonstrated that the expression levels of dihydrodiol dehydrogenase and solute carrier family 7, member 11 gene were significantly associated with patient survival, 269 patients with liver hepatocellular carcinoma from The Cancer Genome Atlas database. To the best of our knowledge, this was the first study to provide evidence that PZH affects circRNA expression levels, which may serve important roles in PZH-treated fibrotic liver through the regulation of functional gene expression. In conclusion, the present study provided new insights into the mechanism underlying the pathogenesis of liver fibrosis and identified potential novel, efficient, therapeutic targets against liver injury.

Identification of two Sel1-like proteins in SPI-19 of Salmonella enterica serovar Pullorum that can mediate bacterial infection through T3SS

The type VI secretion system (T6SS) encoded by Salmonella Pathogenicity Island 19 (SPI-19) has been confirmed to be involved in bacterial infection or colonization in hosts and in the inhibition of the host T-cell immune response. However, deletion of the core genes (clpV, vgrG, and hcp2) encoding the T6SS apparatus does not affect the phenotypes caused by SPI-19-encoded T6SS. As Salmonella infection in host cells and survival in chickens are closely associated with the type III secretion system (T3SS), RNA-Seq was performed, and the results revealed that most T3SS genes were downregulated in the C79–13ΔSPI-19 mutant. To identify the SPI-19 genes involved in regulating T3SS genes expression, we constructed mutants of genes encoding potential regulators (RS09140 and RS09275) or proteins with Sel1-like motifs (RS09150 and RS09155) and analyzed their associated phenotypes. Deletion of RS09150 and RS09155 caused the decreased bacterial infection in avian cells and bacterial colonization in chicken organs. In addition, qRT-PCR results revealed that both mutants showed decreased expression levels of regulatory genes of T3SS. The present findings demonstrate that the two Sel1-like proteins RS09150 and RS09155 in S. Pullorum SPI-19 contribute to bacterial infection in chickens by mediating the expression of T3SS genes, indicating a potential crosstalk between SPI-19 and T3SS in Salmonella.

AZFa Y gene, DDX3Y, evolved novel testis transcript variants in primates with proximal 3´UTR polyadenylation for germ cell specific translation

Translational control is a major level of gene expression regulation in the male germ line. DDX3Y located in the AZFa region of the human Y chromosome encodes a conserved RNA helicase important for translational control at the G1-S phase of the cell cycle. In human, DDX3Y protein is expressed only in premeiotic male germ cells. In primates, DDX3Y evolved a second promoter producing novel testis-specific transcripts. Here, we show primate species-specific use of alternative polyadenylation (APA) sites for these testis-specific DDX3Y transcript variants. They have evolved subsequently in the 3´UTRs of the primates´ DDX3Y transcripts. Whereas a distal APA site (PAS4) is still used for polyadenylation of most DDX3Y testis transcripts in Callithrix jacchus; two proximal APAs (PAS1; PAS2) are used predominantly in Macaca mulatta, in Pan trogloydates and in human. This shift corresponds with a significant increase of DDX3Y protein expression in the macaque testis tissue. In chimpanzee and human, shift to predominant use of the most proximal APA site (PAS1) is associated with translation of these DDX3Y transcripts in only premeiotic male germ cells. We therefore assume evolution of a positive selection process for functional DDX3Y testis transcripts in these primates which increase their stability and translation efficiency to promote its cell cycle balancing function in the human male germ line.