Functional & Integrative Genomics最新文献

Metabolic-associated fatty liver disease (MAFLD) is a globally prevalent liver disorder, and long non-coding RNAs (lncRNAs) play a crucial role in its pathogenesis. However, the specific function of taurine up-regulated gene 1 (TUG1) remains incompletely understood. This study examined the molecular interactions among TUG1, miR-29a-3p, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and sterol regulatory element-binding protein 2 (SREBP-2). Two MAFLD mouse models were established, and liver damage and lipid accumulation were assessed using hematoxylin and eosin (HE) and Oil Red O staining. The expression levels of these factors were measured in liver tissues, and TUG1 expression was knocked down to evaluate its functional impact. The results indicate that TUG1 could bind to miR-29a-3p, thereby regulating the expression of HMGCR and SREBP-2. Tug1 expression is upregulated in livers of MAFLD models compared with control groups, showing a negative correlation with miR-29a-3p and a positive correlation with HMGCR and SREBP-2. Furthermore, the knockdown of Tug1 in mouse livers reduced hepatic lipid deposition significantly. In summary, TUG1 could modulate the SREBP-2/HMGCR pathway by binding to miR-29a-3p, thus influencing lipid metabolism. These findings suggest that TUG1 may serve as a potential therapeutic target for MAFLD.

Breast cancer-related depression (BCRD) is a prevalent comorbidity that markedly reduces quality of life and can negatively influence treatment outcomes. The molecular basis of BCRD remains elusive, particularly the role of the IL-17 signaling pathway in the interaction between breast cancer and depression. We established a BCRD mouse model by inducing breast tumors and administering chronic corticosterone. Transcriptomic analysis was performed on brain and tumor tissues to identify differentially expressed genes (DEGs) associated with BCRD. Functional enrichment analyses were conducted to determine the biological functions and signaling pathways linked to these DEGs. For in vitro validation, lipopolysaccharide (LPS)-stimulated BV2 microglia cells were used to mimic neuroinflammation, and the effects of modulating IL-17 signaling on cellular activation were assessed. In vivo, BCRD mice exhibited increased immobility time in the tail suspension test and reduced sucrose preference, indicative of depressive-like behaviors. Transcriptomic analysis revealed substantial changes in immune-related genes, particularly those involved in the IL-17 signaling pathway. In vitro, LPS stimulation elevated IL-17, NF-κB p65, and other inflammatory markers in BV2 cells, whereas IL-17 inhibition attenuated these responses. Furthermore, we observed increased expression of IL-17 and NF-κB p65 in the brain tissues of BCRD mice, which was associated with increased microglial activation and blood-brain barrier permeability. These findings demonstrate that the IL-17 signaling pathway plays a crucial role in BCRD development, linking breast cancer progression to depressive symptoms through microglia activation and disruption of the blood-brain barrier. Targeting the IL-17 signaling pathway may offer a promising therapeutic strategy for treating BCRD.

Glycine C-acetyltransferase (GCSH), a component of the mitochondrial glycine cleavage system, has been previously linked to cuproptosis or tumor progression, but its role in colorectal cancer (CRC) remains incompletely understood. We analyzed GCSH expression across multiple CRC datasets, including the TCGA dataset (n = 689) and four independent GEO datasets (total n = 709), and validated findings in clinical tissues, blood samples, and CRC cell lines. Functional roles of GCSH were assessed using CCK-8, wound healing, and Transwell assays. Cuproptosis was induce, and evaluated by flow cytometry, Western blotting, and measurement of intracellular Cu²⁺, ROS, and FDX1 levels. The regulatory relationship between GCSH and FDX1, as well as the involvement of the PI3K/AKT pathway, was explored through rescue experiments and molecular docking analysis. The analysis of Bulk RNA-seq data and scRNA-seq datasets revealed the expression and the biological function of GCSH in CRC. The validation experiments confirmed that GCSH was consistently overexpressed in CRC tissues and blood samples, and its expression correlated with distant metastasis. GCSH knockdown inhibited cell viability, migration, and invasion, with minimal effects on apoptosis. Mechanistically, GCSH suppressed cuproptosis by downregulating FDX1 protein and reducing intracellular Cu²⁺ and ROS accumulation. Molecular docking suggested a potential interaction between GCSH and FDX1. Furthermore, GCSH was identified as a downstream effector of PI3K/AKT pathway, mediating its protective effect against cuproptosis. GCSH promotes CRC progression and confers resistance to cuproptosis via the PI3K/AKT-GCSH/FDX1 axis. These findings identify GCSH as a novel regulator of cuproptosis and a potential therapeutic target in CRC.

Feather follicles are specialized skin appendages that are essential for thermoregulation, protection, and down production in birds, forming through complex genetic and epigenetic interactions during embryogenesis. In this study, we examined skin and follicle development in Hungarian white goose embryos, focusing on dynamic epigenetic-transcriptomic changes. Histology showed smooth epidermis at E10, feather buds at E13, and columnar follicles with medullary tissue and secondary follicles at E18. Transcriptomics revealed 1327 and 1847 DEGs enriched in epidermal development, differentiation, and adhesion. Primordial initiation at E10-E13 featured Wnt, TGF-β, and melanogenesis, whereas follicle formation at E13-E18 involved lipid metabolism and VEGF signaling. Keratinization genes were continuously upregulated, and Wnt, Shh, and muscle pathways were activated late. Key regulators included LEF1, MSX2, and FOXN1. ATAC-seq showed dynamic chromatin accessibility, stage-specific promoter openness, and motifs for YY1, KLF5, and KLF4. Differentially accessible regions enriched genes in Wnt and TGF-β signaling, cell adhesion, and mitophagy, shifting from proliferation and basic metabolism at E10-E13 to differentiation, lipid metabolism, and homeostasis at E13-E18. Integrated analyses linked fatty acid metabolism, MAPK, and FoxO signaling to differentiation, while downregulation of redox and migration pathways preserved homeostasis. Some fatty acid metabolism and cell polarity genes increased expression despite reduced accessibility at E13-E18, indicating epigenetic pre-programming and post-transcriptional interplay. This work delineates coordinated epigenetic-transcriptional regulation of goose embryonic skin and feather follicle morphogenesis, offering insights for avian and vertebrate skin appendage studies.

Small peptides (SPs) are critical signaling molecules that regulate a wide array of biological processes in plants, including growth, development, and immune responses. However, their specific roles in the interaction between citrus and Candidatus Liberibacter asiaticus (CLas), the causal agent of the devastating huanglongbing (HLB) disease, remain largely unexplored. This study presents a comprehensive genome-wide identification and characterization of SPs in Citrus sinensis. We identified 5,854 transcripts encoding SPs, constituting 11.81% of the total annotated transcripts. Through comparative transcriptome analysis, we identified 422 SPs that were differentially expressed upon CLas infection, with 217 being up-regulated and 205 down-regulated. Bioinformatic analyses revealed that these responsive SPs are involved in key biological processes such as hormone signaling, plant-pathogen interaction, and immune response activation. A focused screen for small secretory peptides (SSPs) among the up-regulated SPs led to the identification of several members of the Phytosulfokine (PSK) family, including CsPSK1, CsPSK2, and CsPSK4, as prominent HLB-responsive candidates. We experimentally validated that these CsPSKs are secreted into the apoplast, a critical interface for plant-pathogen interactions. Functional characterization through virus-induced gene silencing (VIGS) of the PSK homolog in Nicotiana benthamiana resulted in compromised resistance to Pseudomonas syringae. Conversely, transient overexpression of CsPSK1, CsPSK2, and CsPSK4 in C. sinensis significantly enhanced resistance to Xanthomonas citri subsp. citri (Xcc). These findings collectively demonstrate that CsPSKs are positive regulators of plant immunity and play a conserved role in defense against bacterial pathogens. Furthermore, this research provides insights into the molecular functions of SPs in citrus defense and identifies CsPSKs as potential targets for further investigation in HLB management.

One of the most prevalent malignant tumors in the male genitourinary system is prostate cancer (PCa). The health of men is seriously threatened by the lack of appropriate treatment options for advanced prostate cancer. As E3 ubiquitin ligases, the TRIM family is essential for the development and spread of tumors. Of them, TRIM27 plays a crucial role as a fundamental member of the TRIM family. The tumor immune microenvironment was closely linked to high expression of TRIM27, which was found to be an independent risk factor for a poor prognosis in PCa. Additional in vitro tests verified that TRIM27 stimulates the growth of tumors by controlling the expression of CANX by ubiquitination through triggering the PI3K/AKT signaling pathway. In the meantime, we used several transcription factor databases to find the transcription factor MYC, which can bind to the TRIM27 promoter region and increase its expression, in order to investigate the upstream regulators of TRIM27. In conclusion, our results show that MYC-regulated TRIM27 upregulation influences cancer development through CANX, offering new therapeutic targets and avenues for investigation in the detection and management of PCa.