Search Results (10)

MicroRNAs (miRNAs), as an integral component of gene regulatory networks, play a critical role in post-transcriptional regulation, maintaining a dynamic balance between miRNA biogenesis and turnover essential for maintaining cellular homeostasis. The regulation of miRNA turnover, particularly through target-directed microRNA degradation (TDMD), is emerging as a key mechanism in gene expression control in response to physiological, developmental, and environmental changes. This process is mediated by the ubiquitin–proteasome system (UPS), where the E3 ligase ZSWIM8 functions as an adaptor to facilitate the recognition and degradation of Argonaute (AGO) proteins, essential components of the miRNA-induced silencing complex (miRISC), thus negatively regulating gene expression. The ZSWIM8–UPS axis contributes to the precise modulation of miRNA levels by targeting AGO proteins for degradation, thereby influencing miRNA stability and function. This review summarizes the mechanisms underlying ZSWIM8-mediated TDMD, its molecular interactions, and the potential therapeutic applications of targeting miRNA turnover pathways. By understanding the regulation of miRNA degradation, we aim to inform future strategies for the clinical manipulation of miRNA-based therapeutics. Full article

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring—including altered vocalizations, reduced sociability, and increased repetitive grooming—without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including Homer1 and Zswim6. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative Homer1 promoter, correlating with increased expression of the short isoform Homer1a, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring’s brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk. Full article

The growth and development of muscle tissue play a pivotal role in the economic value and quality of meat in agricultural animals, garnering close attention from breeders and researchers. The quality and palatability of muscle tissue directly determine the market competitiveness of meat products and the satisfaction of consumers. Therefore, a profound understanding and management of muscle growth is essential for enhancing the overall economic efficiency and product quality of the meat industry. Despite this, systematic research on muscle development-related genes across different species still needs to be improved. This study addresses this gap through extensive cross-species muscle transcriptome analysis, combined with interpretable machine learning models. Utilizing a comprehensive dataset of 275 publicly available transcriptomes derived from porcine, bovine, and ovine muscle tissues, encompassing samples from ten distinct muscle types such as the semimembranosus and longissimus dorsi, this study analyzes 113 porcine (n = 113), 94 bovine (n = 94), and 68 ovine (n = 68) specimens. We employed nine machine learning models, such as Support Vector Classifier (SVC) and Support Vector Machine (SVM). Applying the SHapley Additive exPlanations (SHAP) method, we analyzed the muscle transcriptome data of cattle, pigs, and sheep. The optimal model, adaptive boosting (AdaBoost), identified key genes potentially influencing muscle growth and development across the three species, termed SHAP genes. Among these, 41 genes (including NANOG, ADAMTS8, LHX3, and TLR9) were consistently expressed in all three species, designated as homologous genes. Specific candidate genes for cattle included SLC47A1, IGSF1, IRF4, EIF3F, CGAS, ZSWIM9, RROB1, and ABHD18; for pigs, DRP2 and COL12A1; and for sheep, only COL10A1. Through the analysis of SHAP genes utilizing Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, relevant pathways such as ether lipid metabolism, cortisol synthesis and secretion, and calcium signaling pathways have been identified, revealing their pivotal roles in muscle growth and development. Full article

Semen traits play a key role in the pig industry because boar semen is widely used in purebred and crossbred pigs. The production of high-quality semen is crucial to ensuring a good result in artificial insemination. With the wide application of artificial insemination in the pig industry, more and more attention has been paid to the improvement of semen traits by genetic selection. The purpose of this study was to identify the genetic regions and candidate genes associated with semen traits of Duroc boars. We used weighted single-step GWAS to identify candidate genes associated with sperm motility, sperm progressive motility, sperm abnormality rate and total sperm count in Duroc pigs. In Duroc pigs, the three most important windows for sperm motility—sperm progressive motility, sperm abnormality rate, and total sperm count—explained 12.45%, 9.77%, 15.80%, and 12.15% of the genetic variance, respectively. Some genes that are reported to be associated with spermatogenesis, testicular function and male fertility in mammals have been detected previously. The candidate genes CATSPER1, STRA8, ZSWIM7, TEKT3, UBB, PTBP2, EIF2B2, MLH3, and CCDC70 were associated with semen traits in Duroc pigs. We found a common candidate gene, STRA8, in sperm motility and sperm progressive motility, and common candidate genes ZSWIM7, TEKT3 and UBB in sperm motility and sperm abnormality rate, which confirms the hypothesis of gene pleiotropy. Gene network enrichment analysis showed that STRA8, UBB and CATSPER1 were enriched in the common biological process and participated in male meiosis and spermatogenesis. The SNPs of candidate genes can be given more weight in genome selection to improve the ability of genome prediction. This study provides further insight into the understanding the genetic structure of semen traits in Duroc boars. Full article

Background: The expression of human germline genes is restricted to the germ cells of the gonads, which produce sperm and eggs. The germline genes involved in testis development and potentially activated in cancer cells are known as cancer-testis (CT) genes. These genes are potential therapeutic targets and biomarkers, as well as drivers of the oncogenic process. CT genes can be reactivated by treatment with drugs that demethylate DNA. The majority of the existing literature on CT gene activation focuses on X-chromosome-produced CT genes. We tested the hypothesis that epigenetic landscape changes, such as DNA methylation, can alter several CT gene expression profiles in cancer and germ cells. Methods: Colon cancer (CC) cell lines were treated with the DNA methyltransferase inhibitor (DNMTi) 5-aza-2’-deoxycytidine, or with the histone deacetylase inhibitor (HDACi) trichostatin A (TSA). The effects of these epigenetic treatments on the transcriptional activation of previously published CT genes (CTAG1A, SCP2D1, TKTL2, LYZL6, TEX33, and ACTRT1) and testis-specific genes (NUTM1, ASB17, ZSWIM2, ADAM2, and C10orf82) were investigated. Results: We found that treatment of CC cell lines with 5-aza-2’-deoxycytidine or TSA correlated with activation of X-encoded CT genes and non-X-encoded CT genes in somatic (non-germline) cells. Conclusion: These findings confirm that a subset of CT genes can be regulated by hypomethylating drugs and subsequently provide a potential therapeutic target for cancer. Full article

Objective: We investigated the possible modifying effect of obesity on the association of matrix metalloproteinase (MMP) gene polymorphisms with breast cancer (BC) risk. Methods: A total of 1104 women divided into two groups according to their body mass index (BMI): BMI ≥ 30 (119 BC, and 190 control) and BMI < 30 (239 BC, and 556 control) were genotyped for specially selected (according to their association with BC in the previous study) 10 single-nucleotide polymorphisms (SNP) of MMP1, 2, 3, 8, and 9 genes. Logistic regression association analysis was performed in each studied group of women (with/without obesity). Functional annotation of BC-correlated MMP polymorphic variants was analyzed by in silico bioinformatics. Results: We observed significant differences in the involvement of MMP SNPs in BC in obese and non-obese women. Polymorphic loci MMP9 (c.836 A > G (rs17576) and c. 1721 C > G (rs2250889)) were BC-protective factors in obese women (OR 0.71, allelic model, and OR 0.55, additive model, respectively). Genotypes TT MMP2 (c.-1306 C > T,rs243865) and AA MMP9 (c. 1331-163 G > A,rs3787268) determined BC susceptibility in non-obese women (OR 0.31, and OR 2.36, respectively). We found in silico substantial multidirectional influences on gene expression in adipose tissue BC-related polymorphic loci: BC risk allele A-rs3787268 in non-obese women is associated with low expression NEURL2, PLTP, RP3-337O18.9, SPATA25, and ZSWIM1, whereas BC risk allele A-rs17576 in obese women is associated with high expression in the same genes in visceral and/or subcutaneous adipose. Conclusions: our study indicated that obesity has a significant modifying effect on the association of MMP genes with BC risk in postmenopausal women. Full article

Objective: Bitter or sweet beverage perception is associated with alterations in brain structure and function. Our aim is to analyze the genetic association between bitter or sweet beverage perception and human brain proteins. Materials and methods: In our study, 8356 and 11,518 proteins were first collected from two reference datasets of human brain proteomes, the ROS/MAP and Banner. The bitter or sweet beverage perception-related proteome-wide association studies (PWAS) were then conducted by integrating recent genome-wide association study (GWAS) data (n = 422,300) of taste perception with human brain proteomes. The human brain gene expression profiles were collected from two reference datasets, including the brain RNA-seq (CBR) and brain RNA-seq splicing (CBRS). The taste perception-related transcriptome-wide association studies (TWAS) were finally performed by integrating the same GWAS data with human brain gene expression profiles to validate the PWAS findings. Results: In PWAS, four statistically significant proteins were identified using the ROS/MAP and then replicated using the Banner reference dataset (all permutated p < 0.05), including ABCG2 for total bitter beverages and tea, CPNE1 for total bitter beverage, ACTR1B for artificially sweetened beverages, FLOT2 for alcoholic bitter beverages and total sweet beverages. In TWAS analysis, six statistically significant genes were detected by CBR and confirmed by the CBRS reference dataset (all permutated p < 0.05), including PIGG for total bitter beverages and non-alcoholic bitter beverages, C3orf18 for total bitter beverages, ZSWIM7 for non-alcoholic bitter beverages, PEX7 for coffee, PKP4 for tea and RPLP2 for grape juice. Further comparison of the PWAS and TWAS found three common statistically significant proteins/genes identified from the Banner and CBR reference datasets, including THBS4 for total bitter beverages, CA4 for non-alcoholic bitter beverages, LIAS for non-grape juices. Conclusions: Our results support the potential effect of bitter or sweet beverage perception on brain function and identify several candidate brain proteins for bitter or sweet beverage perception. Full article

Most genetic variants are rare and specific to the population, highlighting the importance of characterizing local population genetic diversity. Many countries have initiated population-based whole-genome sequencing (WGS) studies. Genomic variation within Lithuanian families are not available in the public databases. Here, we describe initial findings of a high-coverage (an average of 36.27×) whole genome sequencing for 25 trios of the Lithuanian population. Each genome on average carried approximately 4,701,473 (±28,255) variants, where 80.6% (3,787,626) were single nucleotide polymorphisms (SNPs), and the rest 19.4% were indels. An average of 12.45% was novel according to dbSNP (build 150). The WGS structural variation (SV) analysis identified on average 9133 (±85.10) SVs, of which 95.85% were novel. De novo single nucleotide variation (SNV) analysis identified 4417 variants, where 1.1% de novo SNVs were exonic, 43.9% intronic, 51.9% intergenic, and the rest 3.13% in UTR or downstream sequence. Three potential pathogenic de novo variants in the ZSWIM8, CDC42EP1, and RELA genes were identified. Our findings provide useful information on local human population genomic variation, especially for de novo variants, and will be a valuable resource for further genetic studies, and medical implications. Full article

Bovine juvenile angiomatosis (BJA) comprises a group of single or multiple proliferative vascular anomalies in the skin and viscera of affected calves. The purpose of this study was to characterize the clinicopathological phenotype of a 1.5-month-old Simmental calf with multiple cutaneous, subcutaneous, and visceral vascular hamartomas, which were compatible with a generalized form of BJA, and to identify genetic cause for this phenotype by whole-genome sequencing (WGS). The calf was referred to the clinics as a result of its failure to thrive and the presence of multiple cutaneous and subcutaneous nodules, some of which bled abundantly following spontaneous rupture. Gross pathology revealed similar lesions at the inner thoracic wall, diaphragm, mediastinum, pericardium, inner abdominal wall, and mesentery. Histologically, variably sized cavities lined by a single layer of plump cells and supported by a loose stroma with occasional acute hemorrhage were observed. Determined by immunochemistry, the plump cells lining the cavities displayed a strong cytoplasmic signal for PECAM-1, von Willebrand factor, and vimentin. WGS revealed six private protein-changing variants affecting different genes present in the calf and absent in more than 4500 control genomes. Assuming a spontaneous de novo mutation event, one of the identified variants found in the PREX1, UBE3B, PCDHGA2, and ZSWIM6 genes may represent a possible candidate pathogenic variant for this rare form of vascular malformation. Full article

Gene expression within human glioblastomas were analyzed from data on 20,083 genes entered into the on-line Human Protein Atlas. In selecting genes that are strongly expressed within normal human brain tissue, 58 genes were identified from a search of the 20,083 entries that were rated as showing 90% or greater intensity of expression within normal brain tissues. Of these 58, a subset of 48 genes was identified that not only had expression data for human glioblastomas but also for the human glioblastoma cell line U-251. Four of these 48 selected genes were found to be strongly expressed within the cytoplasm when assessed by both histologic sampling of high grade glioma patient cases as well as U-251 glioblastoma cell line immunofluoresence analysis. These four human genes are: AGBL2 (ATP/GTP binding protein-like 2), BLOC1S6 (biogenesis of lysosomal organelles complex-1, subunit 6), MAP1A (microtubule-associated protein 1A) and ZSWIM5 (zinc finger, SWIM-type containing 5, also known as KIAA1511). Further research is advocated to investigate the role of ZSWIM5 and AGBL2 in glioma cell biology. Full article