Functional & Integrative Genomics最新文献

Clustered miRNAs consist of two or more miRNAs transcribed together and may coordinately regulate gene expression. Differential expression of clustered miRNAs is found to be controlled by crosstalk of genetic or epigenetic mechanisms. It has been demonstrated that clustered miRNA expression patterns greatly impact cancer cell progression. With the CmirC initiative, we initially developed a comprehensive database to identify copy number variation (CNV) driven clustered miRNAs in cancer. Now, we extended the analysis and identified three miRNAs, mir-96, mir-183, and mir-21, were found to be significantly upregulated in 17 cancer types. Further, CmirC is now upgraded to determine the impact of changes in the DNA methylation status at clustered miRNAs by utilizing The Cancer Genomic Atlas (TCGA) cancer datasets. We examined specific methylation datasets from 9,639 samples, pinpointing 215,435 methylation sites and 27,949 CpG islands with miRNA cluster information. The integrated analysis identified 34 clusters exhibiting differentially methylated CpG sites across 14 cancer types. Furthermore, we determined that CpG islands in the promoter region of 20 miRNA clusters could play a regulatory role. Along with ensuring a straightforward and convenient user experience, CmirC has been updated with improved data browsing and analysis functionalities, as well as enabled hyperlinks to literature and miR-cancer databases. The enhanced version of CmirC is anticipated to play an important role in providing information on the regulation of clustered miRNA expression, and their targeted oncogenes and tumor suppressors. The newly updated version of CmirC is available at https://slsdb.manipal.edu/cmirclust/ .

Multiple abiotic stresses like extreme temperatures, water shortage, flooding, salinity, and exposure to heavy metals are confronted by crop plants with changing climatic patterns. Prolonged exposure to these adverse environmental conditions leads to stunted plant growth and development with significant yield loss in crops. CRISPR-Cas9 genome editing tool is being frequently employed to understand abiotic stress-responsive genes. Noteworthy improvements in CRISPR-Cas technology have been made over the years, including upgradation of Cas proteins fidelity and efficiency, optimization of transformation protocols for different crop species, base and prime editing, multiplex gene-targeting, transgene-free editing, and graft-based heritable CRISPR-Cas9 approaches. These developments helped to improve the knowledge of abiotic stress tolerance in crops that could potentially be utilized to develop knock-out varieties and over-expressed lines to tackle the adverse effects of altered climatic patterns. This review summarizes the mechanistic understanding of heat, drought, salinity, and metal stress-responsive genes characterized so far using CRISPR-Cas9 and provides data on potential candidate genes that can be exploited by modern-day biotechnological tools to develop transgene-free genome-edited crops with better climate adaptability. Furthermore, the importance of early-maturing crop varieties to withstand abiotic stresses is also discussed in this review.

Background: Macrophages are the main inflammatory cells involved in kidney injury and play a significant role in the development of acute kidney injury (AKI) and progression of chronic kidney disease (CKD). Emodin is believed to stabilize macrophage homeostasis under pathological conditions. The objective of this study aimed to explore the underlying mechanisms and effects of Emodin on M1 macrophages.

Methods: Network pharmacology methods were used to predict target proteins associated with renal injury and identify the pathways affected by emodin. RAW264.7 macrophages were induced into M1 polarization using LPS and then treated with emodin at 20, 40, and 80 µM. The effects of emodin on cell viability, cytokines (IL-1β, IL-6, TNF-α), M1 macrophage markers (F4/80 + CD86+), and the EGFR/MAPK pathway were evaluated. Additionally, we transfected RAW264.7 cells with an EGFR shRNA interference lentivirus to assess its effects on RAW264.7 cells function and MAPK pathway. After RAW264.7 cells were passaged to expanded culture and transfected with EGFR-interfering plasmid, macrophages were induced to polarize towards M1 with LPS and then treated with 80 µM emodin. CKD modeling was performed to test how emodin is regulated during CKD.

Results: There are 15 common targets between emodin and kidney injury, of which the EGFR/MAPK pathway is the pathway through which emodin affects macrophage function. Emodin significantly reduced the levels of IL-6, IL-1β and TNF-α (p < 0.05) and the ratio of M1 macrophage surface markers F4/80 + CD86+ (p < 0.01) in the supernatant of RAW264.7 cells in a dose-dependent manner. Furthermore, the inhibitory effect of emodin on RAW264.7 cells was achieved by interfering with the EGFR/MAPK pathway. Moreover, emodin also affected the mRNA and protein expression of EGFR and Ras, leading to a decrease in the rate of M1 macrophages, thus inhibiting the pro-inflammatory effect of M1 macrophages. The addition of emodin reduced the rate of M1 macrophages in CKD and inhibited the further polarization of M1 macrophages, thus maintaining the pro-inflammatory and anti-inflammatory homeostasis in CKD, and these effects were achieved by emodin through the control of the EGRF/ERK pathway.

Conclusion: Emodin attenuates M1 macrophage polarization and pro-inflammatory responses via the EGFR/MAPK signalling pathway. And the addition of emodin maintains pro- and anti-inflammatory homeostasis, which is important for maintaining organ function and tissue repair.

Circular RNAs (circRNAs) are circularized single-stranded ribonucleic acids that interacts with DNA, RNA, and proteins to play critical roles in cell biology. CircRNAs regulate microRNA content, gene expression, and may code for specific peptides. Indeed, circRNAs are differentially expressed in neurodegenerative disorders like Parkinson's disease (PD), playing a potential role in the mechanisms of brain pathology. The RNA molecules with aberrant expression in the brain can cross the blood-brain barrier and reach the bloodstream, which enable their use as non-invasive PD disease biomarker. Promising targets with valuable discriminatory ability in combined circRNA signatures include MAPK9_circ_0001566, SLAIN1_circ_0000497, SLAIN2_circ_0126525, PSEN1_circ_0003848, circ_0004381, and circ_0017204. On the other hand, regular exercises are effective therapy for mitigating PD symptoms, promoting neuroprotective effects with epigenetic modulation. Aerobic exercises slow symptom progression in PD by improving motor control, ameliorating higher functions, and enhancing brain activity and neuropathology. These improvements are accompanied by changes circRNA expression, including hsa_circ_0001535 (circFAM13B) and hsa_circ_0000437 (circCORO1C). The sensitivity of current methods for detecting circulating circRNAs is considered a limitation. While amplification kits already exist for low-abundant microRNAs, similar kits are needed for circRNAs. Alternatively, the use of digital PCR can help overcome this constraint. The current review examines the potential use of circRNAs as non-invasive biomarkers of PD and to assess the effects of rehabilitation. Although circRNAs hold promise as targets for PD diagnosis and therapeutics, further validation is needed before their clinical implementation.

Genetically modified (GM) crops, expressing Bacillus thuringiensis (Bt) insecticidal toxins, have substantially transformed agriculture. Despite rapid adoption, their environmental and economic benefits face scrutiny due to unsustainable agricultural practices and the emergence of resistant pests like Spodoptera frugiperda, known as the fall armyworm (FAW). FAW's adaptation to Bt technology in corn and cotton compromises the long-term efficacy of Bt crops. To advance the understanding of the genetic foundations of resistance mechanisms, we conducted an exploratory comparative transcriptomic analysis of two divergent FAW populations. One population exhibited practical resistance to the Bt insecticidal proteins Cry1A.105 and Cry2Ab2, expressed in the genetically engineered MON-89Ø34 - 3 maize, while the other population remained susceptible to these proteins. Differential expression analysis supported that Cry1A.105 and Cry2Ab2 significantly affect the FAW physiology. A total of 247 and 254 differentially expressed genes were identified in the Cry-resistant and susceptible populations, respectively. By integrating our findings with established literature and databases, we underscored 53 gene targets potentially involved in FAW's resistance to Cry1A.105 and Cry2Ab2. In particular, we considered and discussed the potential roles of the differentially expressed genes encoding ABC transporters, G protein-coupled receptors, the P450 enzymatic system, and other Bt-related detoxification genes. Based on these findings, we emphasize the importance of exploratory transcriptomic analyses to uncover potential gene targets involved with Bt insecticidal proteins resistance, and to support the advantages of GM crops in the face of emerging challenges.

In this paper, genomics and precision medicine have witnessed remarkable progress with the advent of high-throughput sequencing technologies and advances in data analytics. However, because of the data's great dimensionality and complexity, the processing and interpretation of large-scale genomic data present major challenges. In order to overcome these difficulties, this research suggests a novel Intelligent Mutation-Based Evolutionary Optimization Algorithm (IMBOA) created particularly for applications in genomics and precision medicine. In the proposed IMBOA, the mutation operator is guided by genome-based information, allowing for the introduction of variants in candidate solutions that are consistent with known biological processes. The algorithm's combination of Differential Evolution with this intelligent mutation mechanism enables effective exploration and exploitation of the solution space. Applying a domain-specific fitness function, the system evaluates potential solutions for each generation based on genomic correctness and fitness. The fitness function directs the search toward ideal solutions that achieve the problem's objectives, while the genome accuracy measure assures that the solutions have physiologically relevant genomic properties. This work demonstrates extensive tests on diverse genomics datasets, including genotype-phenotype association studies and predictive modeling tasks in precision medicine, to verify the accuracy of the proposed approach. The results demonstrate that, in terms of precision, convergence rate, mean error, standard deviation, prediction, and fitness cost of physiologically important genomic biomarkers, the IMBOA consistently outperforms other cutting-edge optimization methods.

Prostate cancer is a major medical problem for men worldwide. Advanced prostate cancer is currently incurable. Recently, much attention was paid to the role of GPC2 in the field of oncology. Nevertheless, there have been no investigations of GPC2 and its regulatory mechanism in prostate cancer. Here, we revealed a novel action of GPC2 and a tumor promoting mechanism in prostate cancer. GPC2 was upregulated in prostate cancer tissues and cell lines. Higher expression of GPC2 was correlated with higher Gleason score, lymphatic metastasis, and worse overall survival in prostate cancer patients. Decreased expression of GPC2 inhibited cell proliferation, migration, and invasion in prostate cancer, whereas GPC2 overexpression promoted these properties. Mechanistically, GPC2 promoted the activation of PI3K/AKT signaling pathway through MDK. The rescue assay results in prostate cancer cells demonstrated that overexpression of MDK could attenuate GPC2 knockdown induced inactivation of PI3K/AKT signaling and partly reverse GPC2 knockdown induced inhibition of cell proliferation, migration, and invasion. In all, our study identified GPC2 as an oncogene in prostate cancer. GPC2 promoted prostate cancer cell proliferation, migration, and invasion via MDK-mediated activation of PI3K/AKT signaling pathway. GPC2 might be a promising prognosis predictor and potential therapeutic target in prostate cancer.

Colorectal cancer (CRC) is a prevalent malignancy affecting the human digestive tract. Triptonide has been shown to have some anticancer activity, but its effect in CRC is vague. Herein, we examined the effect of triptonide on CRC. In this study, the results of bioinformatics analysis displayed that triptonide may regulate ferroptosis in CRC by modulating GPX4 and SLC7A11. In HCT116 and LoVo cells, the expression levels of GPX4 and SLC7A11 were significantly reduced after triptonide management versus the control group. Triptonide inhibited proliferation, but promoted ferroptosis in CRC cells. SLC7A11 upregulation overturned the effects of triptonide on proliferation and ferroptosis in CRC cells. Triptonide inhibited activation of the PI3K/AKT/Nrf2 signaling in CRC cells. Activation of the PI3K/AKT signaling or Nrf2 upregulation overturned the effects of triptonide on proliferation and ferroptosis in CRC cells. Triptonide suppressed CRC cell growth in vivo by modulating SLC7A11 and GPX4. In conclusion, Triptonide repressed proliferation and facilitated ferroptosis of CRC cells by repressing the SLC7A11/GPX4 axis through inactivation of the PI3K/AKT/Nrf2 signaling.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. It has been proven that long non-coding RNAs (lncRNAs) play an essential role in regulating HCC progression. However, the involvement of LINC01094 in regulating epithelial-mesenchymal transition (EMT) in HCC remains unclear. LINC01094 expression in HCC patients was retrieved from the Cancer Genome Atlas database. Overexpressing and downregulating LINC01094 were conducted to investigate its biological functions using Hep3B, SNU-387, and HuH-7 cells. Western blotting and morphological observation were performed to study the EMT in HCC cells. Transwell assay was adopted to determine the migration and invasion of HCC cells. The underlying mechanism of competitive endogenous RNAs (ceRNAs) was investigated using bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction, and rescue experiments. Elevated LINC01094 expression was observed in HCC and associated with a poor prognosis. Knockdown of LINC01094 expression in SNU-387 and HuH-7 cells could inhibit migration, invasion, and EMT markers. Overexpression of LINC01094 indicated that LINC01094 promoted EMT via the TGF-β/SMAD signaling pathway. The bioinformatics analysis revealed that miR-122-5p was a target of LINC01094. The miRWalk database analysis showed that TGFBR2, SMAD2, and SMAD3 were downstream targets of miR-122-5p. Mechanically, LINC01094 acted as a ceRNA that facilitated HCC metastasis by sponging miR-122-5p to regulate the expression of TGFBR2, SMAD2, and SMAD3. Further, TGF-β1 could enhance the expression of LINC01094, forming a positive feedback loop. TGF-β1-induced LINC01094 expression promotes HCC cell migration and invasion by targeting the miR-122-5p/TGFBR2-SMAD2-SMAD3 axis. LINC01094 may be a potential prognostic biomarker and therapeutic target for HCC metastasis.

MDS1 and EVI1 complex locus (MECOM), a transcription factor encoding several variants, has been implicated in progression of ovarian cancer. The function of regulatory regions in regulating MECOM expression in ovarian cancer is not fully understood. In this study, MECOM expression was evaluated in ovarian cancer cell lines treated with bromodomain and extraterminal (BET) inhibitor JQ-1. Oncogenic phenotypes were assayed using assays of CCK-8, colony formation, wound-healing and transwell. Oncogenic phenotypes were estimated in stable sgRNA-transfected OVCAR3 cell lines. Xenograft mouse model was assayed via subcutaneous injection of enhancer-deleted OVCAR3 cell lines. The results displayed that expression of MECOM is downregulated in cell lines treated with JQ-1. Data from published ChIP-sequencing (H3K27Ac) in 3 ovarian cancer cell lines displayed a potential enhancer around the first exon. mRNA and protein expression were downregulated in OVCAR3 cells after deletion of the MECOM enhancer. Similarly, oncogenic phenotypes both in cells and in the xenograft mouse model were significantly attenuated. This study demonstrates that JQ-1 can inhibit the expression of MECOM and tumorigenesis. Deletion of the enhancer activity of MECOM has an indispensable role in inhibiting ovarian cancer progress, which sheds light on a promising opportunity for ovarian cancer treatment through the application of this non-coding DNA deletion.