Search Results (23)

Lymphocyte activation gene 3 (LAG3) is an inhibitory receptor and the interaction between fibrinogen-like protein 1 and LAG3 can inhibit the anti-tumor effect of T cells both in vivo and in vitro, which was regarded as a new immune evasion mechanism. Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, is an infectious disease characterized by reproductive disorders in pregnant sows and gilts and respiratory problems in pigs of all ages, seriously impacting the pig industry worldwide. In this study, monoclonal antibodies (mAbs) against porcine LAG3 (pLAG3) were developed, and one mAb (1C2) showed good reactivity with pLAG3 on PHA-activated porcine peripheral blood lymphocytes. Epitope mapping showed the epitope recognized by mAb 1C2 was located at amino acid residues 214–435 of pLAG3. LAG3 expression in the tissues of PRRSV-infected pigs was detected, using mAb 1C2 as the primary antibody, and the results revealed that PRRSV infection caused a marked increase in LAG3 expression compared to the control group. Interference of LAG3 expression on PHA-activated lymphocytes promoted PRRSV replication in the co-culture system of monocyte-derived dendritic cells and lymphocytes, whereas overexpression of LAG3 or blocking of the LAG3 signal with mAb 1C2 inhibited PRRSV replication, indicating that PRRSV infection activates the LAG3-signaling pathway, suggesting that this pathway plays an important role in PRRSV pathogenesis. The results obtained lay the foundation for subsequent research on the role of LAG3 in PRRS and other diseases with persistent infection characteristics. Full article

Background: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity. The aim of this study on mice was to determine the effect of obesity on maternal lipid handling, inflammatory and redox state, and placental oxidative stress, inflammatory signaling, and gene expression relative to female and male fetal growth. Methods: Female mice were fed control or obesogenic high-fat/high-sugar diet (HFHS) from 9 weeks prior to, and during, pregnancy. On day 18.5 of pregnancy, maternal plasma, and liver, placenta, and fetal serum were collected to examine the immune and redox states. The placental labyrinth zone (Lz) was dissected for RNA-sequencing analysis of gene expression changes. Results: the HFHS diet induced, in the dams, hepatic steatosis, oxidative stress (reduced catalase, elevated protein oxidation) and the activation of pro-inflammatory pathways (p38-MAPK), along with imbalanced circulating cytokine concentrations (increased IL-6 and decreased IL-5 and IL-17A). HFHS fetuses were asymmetrically growth-restricted, showing sex-specific changes in circulating cytokines (GM-CSF, TNF-α, IL-6 and IFN-γ). The morphology of the placenta Lz was modified by an HFHS diet, in association with sex-specific alterations in the expression of genes and proteins implicated in oxidative stress, inflammation, and stress signaling. Placental gene expression changes were comparable to that seen in models of intrauterine inflammation and were related to a transcriptional network involving transcription factors, LYL1 and PLAG1. Conclusion: This study shows that fetal growth restriction with maternal obesity is related to elevated oxidative stress, inflammatory pathways, and sex-specific placental changes. Our data are important, given the marked consequences and the rising rates of obesity worldwide. Full article

China has rich genetic resources of local pig breeds. In this study, whole-genome resequencing was performed on five Shanghai local pig breeds, aiming to analyze their population genetic structure and unique genomic characteristics. Tens of millions of single nucleotide variants were obtained through the resequencing of a total of 150 individual pigs from five local pig breeds (Meishan, Fengjing, Shawutou, Pudong White, and Shanghai White) after mapping them with the pig reference genome of Sus scrofa 11.1. The results of admixture structure analysis also clearly demonstrated the genetic differences between the Shanghai local pig breeds and the three commercial pig breeds (Duroc, Landrace, and Yorkshire). The genetic infiltration of Landrace and Yorkshire pig breeds in the SHW breed was detected, which is consistent with the early history of crossbreeding in this breed. Selective sweep analysis between four indigenous Shanghai pig breed populations and three commercial pig breed populations identified 270 and 224 genes with selective signatures in the commercial and indigenous Shanghai pig populations, respectively. Six genes (TGS1, PLAG1, CHCHD7, LCORL, TMEM68, and TMEM8B) were found to be associated with animal growth in the commercial pig population through gene enrichment and protein–protein interaction analysis. In contrast, the MSRB3 gene in the indigenous Shanghai pig population was significantly under selection, which correlated with the long pendulous ear phenotype of the indigenous Shanghai pig population. In conclusion, this study is the first genomic profiling of five representative local pig breeds in Shanghai, which provides molecular genetic data and foundations for better conservation and utilization of local pig breed resources in Shanghai, China. Full article

Mesenchymal stem cells (MSCs) have a high tropism for the hypoxic microenvironment of tumors. The combination of nanoparticles in MSCs decreases tumor growth in vitro as well as in rodent models of cancers in vivo. Covalent conjugation of nanoparticles with the surface of MSCs can significantly increase the drug load delivery in tumor sites. Nanoparticle-based anti-angiogenic systems (gold, silica and silicates, diamond, silver, and copper) prevented tumor growth in vitro. For example, glycolic acid polyconjugates enhance nanoparticle drug delivery and have been reported in human MSCs. Labeling with fluorescent particles (coumarin-6 dye) identified tumor cells using fluorescence emission in tissues; the conjugation of different types of nanoparticles in MSCs ensured success and feasibility by tracking the migration and its intratumor detection using non-invasive imaging techniques. However, the biosafety and efficacy; long-term stability of nanoparticles, and the capacity for drug release must be improved for clinical implementation. In fact, MSCs are vehicles for drug delivery with nanoparticles and also show low toxicity but inefficient accumulation in tumor sites by clearance of reticuloendothelial organs. To solve these problems, the internalization or conjugation of drug-loaded nanoparticles should be improved in MSCs. Finally, CXCR4 may prove to be a promising target for immunotherapy and cancer treatment since the delivery of siRNA to knock down this alpha chemokine receptor or CXCR4 antagonism has been shown to disrupt tumor–stromal interactions. Full article

The pleomorphic adenoma gene 1 (PLAG1) gene, as the major gene responsible for growth, plays a vital role in myogenesis. Meanwhile, the relationship between copy number variation (CNV) of this gene and growth traits in goats remains unclear. Therefore, this study investigated four aspects: bioinformatics analysis, mRNA expression (n = 6), CNV detection (n = 224), and association analysis. The findings indicated that the gene had a large number of conserved motifs, and the gene expression level was higher in fetal goats than in adult goats. Three CNV loci were selected from the database, among which CNV1 was located in the bidirectional promoter region and was associated with goat growth traits. CNV analysis showed that CNV2 and CNV3 of the PLAG1 gene were associated with growth traits such as body weight, heart girth, height at hip cross, and hip width (p < 0.05), with CNV1 loss genotype being the superior genotype, and CNV2 and CNV3 median and gain genotypes of being superior genotypes. This finding further confirms that the PLAG1 gene is the dominant gene for growth traits, which will serve as theoretical guidance for goat breeding. Full article

Chinese Red Steppe Cattle (CRS), a composite cattle breed, is well known for its milk production, high slaughter rate, carcass traits, and meat quality. Nowadays, it is widely bred in Jilin and Hebei Province and the Inner Mongolia Autonomous region. However, the population structure and the genetic basis of prominent characteristics of CRS are still unknown. In this study, we systematically describe their population structure, genetic diversity, and selection signature based on genotyping data from 61 CRS individuals with GGP Bovine 100 K chip. The results showed that CRS cattle had low inbreeding levels and had formed a unique genetic structure feature. Using two complementary methods (including comprehensive haplotype score and complex likelihood ratio), we identified 1291 and 1285 potentially selected genes, respectively. There were 141 genes annotated in common 106 overlapping genomic regions covered 5.62 Mb, including PLAG1, PRKG2, DGAT1, PARP10, TONSL, ADCK5, and BMP3, most of which were enriched in pathways related to muscle growth and differentiation, milk production, and lipid metabolism. This study will contribute to understanding the genetic mechanism behind artificial selection and give an extensive reference for subsequent breeding. Full article

Sheep birth and weaning weights indicate their growth and survival. Thus, identifying molecular genetic markers for early body weight is important in sheep breeding. Pleomorphic adenoma gene 1 (PLAG1) is important for regulating birth weight and body length in mammals; however, its relationship with sheep body weight remains unknown. Here, the 3′-untranslated region (3′-UTR) of the Hu sheep PLAG1 gene was cloned, single nucleotide polymorphisms (SNPs) were screened, genotype–early body weight relationships were analyzed, and the possible molecular mechanism was explored. PLAG1 3′-UTR sequences with five forms of base sequences plus poly(A) tails were detected in Hu sheep and the g.8795C>T mutation was identified. Luciferase reporter assay indicated that the g.8795C>T mutation influenced PLAG1 post-transcriptional activity. miRBase prediction showed that the g.8795C>T mutation was located in the miR-139 seed sequence binding region, and miR-139 overexpression significantly decreased both PLAG1-CC and PLAG1-TT activities. Moreover, the luciferase activity of PLAG1-CC was significantly lower than that of the PLAG1-TT, but miR-139 inhibition substantially increased both PLAG1-CC and PLAG1-TT luciferase activities, suggesting that PLAG1 is the target gene of miR-139. Thus, the g.8795C>T mutation upregulates PLAG1 expression by weakening its binding with miR-139, promoting PLAG1 expression, and increasing Hu sheep birth and weaning weights. Full article

Wanbei pig (WBP) is one of the indigenous pig resources in China and has many germplasm characteristics. However, research on its genome is lacking. To assess the genomic variation, population structure, and selection signatures, we resequenced 18 WBP for the first time and performed a comprehensive analysis with resequenced data of 10 Asian wild boars. In total, 590.03 Gb of data and approximately 41 million variants were obtained. Polymorphism level (θπ) ratio and genetic differentiation (fixation index)-based cross approaches were applied, and 539 regions, which harbored 176 genes, were selected. Functional analysis of the selected genes revealed that they were associated with lipid metabolism (SCP2, APOA1, APOA4, APOC3, CD36, BCL6, ADCY8), backfat thickness (PLAG1, CACNA2D1), muscle (MYOG), and reproduction (CABS1). Overall, our results provide a valuable resource for characterizing the uniqueness of WBP and a basis for future breeding. Full article

The purpose of the current review was to explore and summarize different studies concerning the detection and characterization of candidate genes and genomic regions associated with economically important traits in Hanwoo beef cattle. Hanwoo cattle, the indigenous premium beef cattle of Korea, were introduced for their marbled fat, tenderness, characteristic flavor, and juiciness. To date, there has been a strong emphasis on the genetic improvement of meat quality and yields, such as backfat thickness (BFT), marbling score (MS), carcass weight (CW), eye muscle area (EMA), and yearling weight (YW), as major selection criteria in Hanwoo breeding programs. Hence, an understanding of the genetics controlling these traits along with precise knowledge of the biological mechanisms underlying the traits would increase the ability of the industry to improve cattle to better meet consumer demands. With the development of high-throughput genotyping, genomewide association studies (GWAS) have allowed the detection of chromosomal regions and candidate genes linked to phenotypes of interest. This is an effective and useful tool for accelerating the efficiency of animal breeding and selection. The GWAS results obtained from the literature review showed that most positional genes associated with carcass and growth traits in Hanwoo are located on chromosomes 6 and 14, among which LCORL, NCAPG, PPARGC1A, ABCG2, FAM110B, FABP4, DGAT1, PLAG1, and TOX are well known. In conclusion, this review study attempted to provide comprehensive information on the identified candidate genes associated with the studied traits and genes enriched in the functional terms and pathways that could serve as a valuable resource for future research in Hanwoo breeding programs. Full article

Salivary gland tumors are a heterogeneous group of tumors originating from the major and minor salivary glands. The pleomorphic adenoma (PA), which is the most common subtype, is a benign lesion showing a remarkable morphologic diversity and that, upon recurrence or malignant transformation, can cause significant clinical problems. Cytogenetic studies of >500 PAs have revealed a complex and recurrent pattern of chromosome rearrangements. In this review, we discuss the specificity and frequency of these rearrangements and their molecular/clinical consequences. The genomic hallmark of PA is translocations with breakpoints in 8q12 and 12q13-15 resulting in gene fusions involving the transcription factor genes PLAG1 and HMGA2. Until recently, the association between these two oncogenic drivers was obscure. Studies of the Silver–Russel syndrome, a growth retardation condition infrequently caused by mutations in IGF2/HMGA2/PLAG1, have provided new clues to the understanding of the molecular pathogenesis of PA. These studies have demonstrated that HMGA2 is an upstream regulator of PLAG1 and that HMGA2 regulates the expression of IGF2 via PLAG1. This provides a novel explanation for the 8q12/12q13-15 aberrations in PA and identifies IGF2 as a major oncogenic driver and therapeutic target in PA. These studies have important diagnostic and therapeutic implications for patients with PA. Full article

High-throughput DNA sequencing has allowed for the identification of genomic alterations and their impact on tumor development, progression, and therapeutic responses. In PSCC, for which the incidence has progressively increased worldwide, there are still limited data on the molecular mechanisms involved in the disease pathogenesis. In this study, we characterized the mutational signature of 30 human papillomavirus (HPV)-associated PSCC cases from Latin Americans, using whole-exome sequencing. Copy number variations (CNVs) were also identified and compared to previous array-generated data. Enrichment analyses were performed to reveal disrupted pathways and to identify alterations mapped to HPV integration sites (HPVis) and miRNA–mRNA hybridization regions. Among the most frequently mutated genes were NOTCH1, TERT, TTN, FAT1, TP53, CDKN2A, RYR2, CASP8, FBXW7, HMCN2, and ITGA8. Of note, 92% of these altered genes were localized at HPVis. We also found mutations in ten novel genes (KMT2C, SMARCA4, PTPRB, AJUBA, CR1, KMT2D, NBEA, FAM135B, GTF2I, and CIC), thus increasing our understanding of the potential HPV-disrupted pathways. Therefore, our study reveals innovative targets with potential therapeutic benefits for HPV-associated PSCCs. The CNV analysis by sequencing (CNV-seq) revealed five cancer-associated genes as the most frequent with gains (NOTCH1, MYC, NUMA1, PLAG1, and RAD21), while 30% of the tumors showed SMARCA4 with loss. Additionally, four cancer-associated genes (CARD11, CSMD3, KDR, and TLX3) carried untranslated regions (UTRs) variants, which may impact gene regulation by affecting the miRNAs hybridization regions. Altogether, these data contribute to the characterization of the mutational spectrum and its impact on cellular signaling pathways in PSCC, thus reinforcing the pivotal role of HPV infection in the molecular pathogenesis of these tumors. Full article

Complex evolutionary processes, such as positive selection and introgression can be characterized by in-depth assessment of sequence variation on a whole-genome scale. Here, we demonstrate the combined effects of positive selection and adaptive introgression on genomes, resulting in observed hotspots of runs of homozygosity (ROH) haplotypes on the modern bovine (Bos taurus) genome. We first confirm that these observed ROH hotspot haplotypes are results of positive selection. The haplotypes under selection, including genes of biological interest, such as PLAG1, KIT, CYP19A1 and TSHB, were known to be associated with productive traits in modern Bos taurus cattle breeds. Among the haplotypes under selection, we demonstrate that the CYP19A1 haplotype under selection was associated with milk yield, a trait under strong recent selection, demonstrating a likely cause of the selective sweep. We further deduce that selection on haplotypes containing KIT variants affecting coat color occurred approximately 250 generations ago. The study on the genealogies and phylogenies of these haplotypes identifies that the introgression events of the RERE and REG3G haplotypes happened from Bos indicus to Bos taurus. With the aid of sequencing data and evolutionary analyses, we here report introgression events in the formation of the current bovine genome. Full article

Cutaneous sweat gland tumors are a subset of adnexal neoplasms that derive or differentiate into the sweat apparatus. Their great diversity, rarity, and complex terminology make their pathological diagnosis challenging. Recent findings have revealed a wide spectrum of oncogenic drivers, several of which are of diagnostic interest for pathologists. Most of these molecular alterations are represented by gene fusions, which are shared with other homologous neoplasms occurring in organs containing exocrine glands, such as salivary and breast glands, which show similarities to the sweat apparatus. This review aims to provide a synthesis of the most recent immunohistochemical and molecular markers used for the diagnosis of sweat gland tumors and to highlight their relationship with similar tumors in other organs. It will cover adenoid cystic carcinoma (NFIB, MYB, and MYBL1 fusion), cutaneous mixed tumor (PLAG1 fusion), cylindroma and spiradenoma and their carcinomas thereof (NF-κB activation through CYLD inactivation or ALKP1 hotspot mutation), hidradenoma and hidradenocarcinoma (MAML2 fusion), myoepithelioma (EWSR1 and FUS fusion), poroma and porocarcinoma (YAP1, MAML2, and NUTM1 fusion), secretory carcinoma (ETV6, NTRK3 fusion), tubular adenoma and syringo-cystadenoma papilliferum (HRAS and BRAF activating mutations). Sweat gland tumors for which there are no known molecular abnormalities will also be briefly discussed, as well as potential future developments. Full article

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients’ quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors. Using genomic high-throughput analysis we identified a miRNA signature involved in bone metastasis that also presents potential as a biomarker of PCa progression in human samples. In particular, the downregulation of miR-135b favored the incidence of bone metastases by significantly increasing PCa cells’ migratory capacity. Moreover, the PLAG1, JAKMIP2, PDGFA, and VTI1b target genes were identified as potential mediators of miR-135b’s role in the dissemination to bone. In this study, we provide a genomic signature involved in PCa bone growth, contributing to a better understanding of the mechanisms responsible for this process. In the future, our results could ultimately translate into promising new therapeutic targets for the treatment of lethal PCa. Full article

Adipokines and gastrointestinal tract hormones are important metabolic parameters, and both epigenetic factors and differential gene expression patterns may be associated with the alterations in their concentrations in children. The function of the FTO gene (FTO alpha-ketoglutarate dependent dioxygenase) in the regulation of the global metabolic rate is well described, whereas the influence of protooncogene PLAG1 (PLAG1 zinc finger) is still not fully understood. A cross-sectional study on a group of 26 children with various BMI values (15.3–41.7; median 28) was carried out. The aim was to evaluate the dependencies between the level of methylation and expression of aforementioned genes with the concentration of selected gastrointestinal tract hormones and adipokines in children. Expression and methylation were measured in peripheral blood mononuclear DNA by a microarray technique and a restriction enzyme method, respectively. All peptide concentrations were determined using the enzyme immunoassay method. The expression level of both FTO and PLAG1 genes was statistically significantly related to the concentration of adipokines: negatively for apelin and leptin receptor, and positively for leptin. Furthermore, both FTO methylation and expression negatively correlated with the concentration of resistin and visfatin. Cholecystokinin was negatively correlated, whereas fibroblast growth factor 21 positively correlated with methylation and expression of the FTO gene, while FTO and PLAG1 expression was negatively associated with the level of cholecystokinin and glucagon-like peptide-1. The PLAG1 gene expression predicts an increase in leptin and decrease in ghrelin levels. Our results indicate that the FTO gene correlates with the concentration of hormones produced by the adipose tissue and gastrointestinal tract, and PLAG1 gene may be involved in adiposity pathogenesis. However, the exact molecular mechanisms still need to be clarified. Full article