Functional & Integrative Genomics最新文献

Tobacco black shank disease, caused by Phytophthora nicotianae, is one of the most devastating diseases affecting tobacco growth. Currently, chemical pesticides control is the most rapid and effective method for managing fungal diseases, yet it exerts significant impacts on the environment. Screening natural metabolites from plant that can prevent and control tobacco black shank disease is of great significance in sustainable development of tobacco cultivation. Quercetin is a natural flavonoid compound widely existing in plants and possesses various biological activities, such as antibacterial and antioxidant properties. However, its potential functions in controlling tobacco black shank has not been fully explored. In this study, we found that application of exogenous quercetin could significantly inhibit the growth of P. nicotianae and enhance tobacco resistance to P. nicotianae by enhancing tobacco antioxidant capacity, modulating the expression of cell wall biosynthesis, immune response and hormone signaling transduction related genes. In addition, we found that quercetin treatment could significantly induce the expression of NtMYB4 to enhance plants resistance to P. nicotianae. Furthermore, we found that after inoculation with P. nicotianae, the accumulation of quercetin in the resistant variety was significantly higher than that in the susceptible variety, suggesting its important role in tobacco resistance to P. nicotianae in different varieties. Generally, our study provides new insights into the potential mechanisms by which quercetin promotes tobacco resistance to P. nicotianae, and and lays a theoretical foundation for future direct application of quercetin or breeding of high quercetin content varieties to prevent tobacco black shank disease.

Temozolomide (TMZ) constitutes the first-line chemotherapeutic regimen for glioblastoma (GBM), yet its clinical efficacy remains suboptimal. β-lapachone, a naturally occurring NQO1 inhibitor, has demonstrated potent antitumor activity across multiple malignancies. Based on the critical involvement of nuclear factor-κB (NF-κB) in GBM pathogenesis, this study investigated whether β-lapachone can enhance the antitumor effect of TMZ by targeting the NF-κB pathway using both in vitro and in vivo models. We found that β-lapachone acts synergistically with TMZ to inhibit GBM cell proliferation, epithelial–mesenchymal transition (EMT), and angiogenesis by suppressing NF-κB activation through blockade of p65 nuclear translocation. These results provide a solid preclinical foundation for combining β-lapachone with TMZ as a promising strategy to counteract TMZ resistance in GBM.

Loropetalum chinense var. rubrum is a highly favored ornamental plant in landscaping applications, where its vibrant purplish-red foliage and dense clusters of purplish-red flowers create a striking contrast to the green leaves and white blossoms of its parent species, L. chinense. Despite extensive horticultural utilization, chloroplast genome divergence between L. chinense and its red-leaved variety is poorly characterized. Here, we sequenced and analyzed complete chloroplast genomes of L. chinense and other two horticultural selections of L. chinense var. rubrum exhibiting distinct flower colors. Through comparative genomics, we aimed to identify sequence-level variations and detect potential selection signatures in chloroplast genes. The results showed that the chloroplast genomes ranged from 159,425 to 159,452 bp, with variations primarily driven by insertions and deletions (INDELs) within single-copy regions, while inverted repeat (IR) regions were highly conserved. Three hypervariable regions (trnH-GUG-psbA, ndhD, ycf1 ) enabled the differentiation between L. chinense and its horticultural variety rubrum, and six other regions (e.g., psbA, rps16-trnQ-UUG, atpF) exhibited intraspecific variation unique to the latter. Furthermore, we detected signals of positive selection in the rpoB gene, which contains a micro-inversion unique to the light red-flowered individual. This inversion resulted in five amino acid substitutions, suggesting potential functional consequences for the gene product. These findings enhance our understanding of chloroplast genome evolution in L. chinense and provide valuable genetic tools for phylogenetic and population genomic studies.

Neonatal hypoxic-ischemic encephalopathy (HIE) affects approximately 0.2%–0.3% of live births in developed countries, and nearly 40% of survivors experience lasting cognitive impairments, often accompanied by circadian rhythm disturbances. To explore the underlying mechanism, we examined the expression changes of miR-9a-5p in a neonatal rat model of hypoxic-ischemic brain damage (HIBD) and assessed its long-term influence on circadian rhythm and cognitive function. The results show that miR-9a-5p is significantly upregulated in the pineal gland of HIBD rats. Dual-luciferase reporter experiments further confirm that miR-9a-5p directly targets Clock. Compared with sham-operated controls, HIBD rats showed a significant reduction in the transcript levels of Clock and other circadian genes, including Per1, Cry1, and Bmal1. Behavioral analyses demonstrated that overexpression of miR-9a-5p disrupted circadian rhythm, accelerating the onset of physical activity. Furthermore, performance in the Morris water maze, open field, and novel object recognition tests indicated that miR-9a-5p overexpression significantly impaired cognitive function and increased anxiety-like behaviors. These findings suggest that miR-9a-5p exerts notable pathological effects in the HIBD model by targeting Clock, and the circadian rhythm genes it regulates may serve as potential therapeutic targets for circadian rhythm-related cognitive dysfunction following HIBD.

Graphical abstract

Schematic diagram illustrating the mechanism by which miR-9a-5p influences circadian rhythm and neurobehavioral outcomes in HIBD through the regulation of the Clock gene.

Oxidative stress (OS), caused by an imbalance between reactive oxygen species (ROS) and antioxidant defenses, has a dual role in cancer: it can both drive tumor growth and trigger cell death. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, are closely linked to this process. ROS influence miRNA production through effects on RNA processing enzymes, transcription factors, and epigenetic changes, while miRNAs in turn regulate ROS levels by targeting key antioxidant pathways such as Nrf2/Keap1, superoxide dismutase, and catalase. This two-way regulation shapes cancer development by controlling proliferation, apoptosis, and metastasis. Understanding this crosstalk provides new opportunities for therapy, including miRNA-based strategies to restore redox balance and improve cancer treatment outcomes. This review summarizes the molecular mechanisms of ROS and miRNA interactions and discusses their implications for cancer pathogenesis and therapeutic targeting.

Graphical abstract

Family with sequence similarity 72 (FAM72) is a protein-coding gene family located on chromosome 1 (chr1) in humans, and its functional roles, particularly in cancer, remain incompletely understood. Chimeric messenger RNA (mRNA) generated by intergenic mRNA trans-splicing (CRTS) is a novel phenomenon increasingly recognized for its involvement in cancer biology. It involves the fusion of two separate mRNA transcripts from different genomic loci, resulting in a chimeric mRNA molecule with altered functions. Since aging-related diseases, including various types of cancer, are major threats to our society, we investigated the functional significance of chimeric FAM72 fusion genes and their potential role in cancer cell proliferation with a focus on intergenic mRNA trans-splicing of FAM72 in cancer. We applied biocomputational analyses to identify chimeric FAM72 fusion genes across various cancer tissues. Whole-genome sequencing (WGS) and next-generation sequencing (NGS) of mRNA (RNA-seq) analysis were applied to identify novel chimeric FAM72 fusion genes at the genome (genomic structural variants or SVs) and/or mRNA level (trans-splicing). Our data supported the occurrence of novel chimeric adiponectin receptor-2 (ADIPOR2) :: FAM72B mRNA transcripts primarily produced through an intergenic mRNA trans-splicing event. Afterwards, we set up a breast cancer tissue-specific cell system to analyze the proliferative and migratory efficacy of cancer cells expressing these novel chimeric ADIPOR2::FAM72B mRNA fusion transcripts. Our findings suggest that the novel chimeric ADIPOR2::FAM72B mRNAs, generated by intergenic mRNA trans-splicing, can act as oncogenic drivers and represent promising diagnostic and therapeutic targets in breast cancer.

Graphical abstract

Ferroptosis is an iron-dependent form of regulated cell death that plays a dual role in cancer progression and suppression. Solute carrier family 7 member 11 (SLC7A11/xCT) is a key regulator of tumor cell ferroptosis that promotes cystine uptake and glutathione synthesis. However, the regulatory mechanisms of ferroptosis remain unclear, which limits its application in cancer therapy. Recent studies have found that non-coding RNAs (ncRNAs), including lncRNAs, miRNAs, and circRNAs, participate in the process of ferroptosis by regulating SLC7A11. In this review, we summarize the mechanisms of ncRNAs that regulate SLC7A11 expression through transcriptional, post-transcriptional, and epigenetic ways to influence ferroptosis in tumor cells. Furthermore, we explore the potential use of the ncRNA/SLC7A11 axis as a therapeutic target for tumors, and introduce new strategies aimed at inducing ferroptosis and overcoming chemotherapy resistance, such as natural compounds targeting ncRNA and nano-delivery systems. This review will enhance our understanding of the potential of ncRNAs targeting SLC7A11 in tumor therapy and offer new approaches to investigating novel tumor diagnostic and therapeutic biochemical indicators in future clinical treatments.

The CRISPR-Cas13 system has emerged as a powerful platform for programmable RNA targeting, offering efficient and sequence-specific silencing of coding and non-coding transcripts. The RNA-targeting capabilities of CRISPR-Cas13 have been harnessed to silence transcripts harbouring pathogenic mutations and combat infectious diseases. However, the molecular basis of on-target and collateral activity are not completely understood, limiting the utility of Cas13 systems. In this study, we delineate the principles for the development of effective crRNAs by targeting DsRed fluorescence reporter and synthetic influenza mRNA in chicken fibroblast DF1 cells. To systematically determine the optimal design for RfxCas13d crRNA, we investigated the minimum length of the crRNA, importance of protospacer flanking sequence, degree of mismatch tolerance, and off target effects. Our data reveal variable knockdown levels between crRNAs, in which several crRNAs achieved over 95% target knockdown. We show that crRNAs exhibit a high degree of tolerance to single-nucleotide mismatches, regardless of their position in the spacer sequence. However, 4-nt mismatches between the spacer and the target significantly reduces targeting efficacy, whereas eight nucleotide mismatches completely abolish the activity of RfxCas13d. Finally, we compared targeting efficiency and collateral activity of two widely used RfxCas13d and HfCas13d variants. Our data extend current understanding of Cas13d-mediated RNA targeting and offer a framework for rational crRNA design to enhance effectiveness in diverse applications, including antiviral strategies.

The purpose of this study is to explore the role in MCTP2 glioblastoma (GBM) relapse and associated therapy target, especially its function on immune suppression together with drug-resistance. We performed transcriptional analysis of primary and recurrent GBM samples from the TCGA and CGGA databases to identify a key regulatory gene in relation to synaptic-related pathways using MCTP2. We used single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analysis of expression in GBM samples to explore the population landscapes as well as tumor region-specific features at the molecular level. Functional studies via Western blotting, colony-formation assays and patient-derived organoid (PDO) models were used to assess the effect of MCTP2-depletion with/without SB52334 treatment in GBM. MCTP2 is significantly up-regulated in recurrent GBM and it correlates with poor survival. In addition, the increased expression of immune checkpoint markers PD-L1 (CD274) and CTLA-4 were significantly associated with high MCTP2 levels, indicating that MCTP2 could affect GBM patients' responses to anti-PD-1/PD-L1 or/and anti-CTLAs therapies. Overexpression of MCTP2 was also related to the increase in drug-resistance, specifically against SB52334. Combining MCTP2 KD with SB52334 significantly decreased primary cell clonogenic potential and organoid viability, suggesting a synergistic effect. MCTP2 plays a distinct role in GBM, acting as a novel facilitator of immune evasion and drug resistance with potential therapeutic implications. Our findings suggest that combining MCTP2 knockdown with SB52334 treatment could enhance the therapeutic efficacy against GBM.

Cytokinins are a class of important plant hormones that are closely associated with processes such as cell division, meristem initiation, and leaf differentiation. Numerous genes involved in cytokinin metabolism and signaling pathways have been reported, and we identified a C2H2 transcription factor that strongly modulates both processes. In this study, we isolated a spontaneous rice mutant displaying wider leaves and thicker roots, thus naming it enlarged leaf and root 1. Through map-based cloning, we mapped ELR1 to chromosome 3 of rice, which encodes a C2H2 zinc-finger protein. It was previously named DROUGHT AND SALT TOLERANCE (DST) or WIDE LEAF 1 (WL1), involved in stress response, leaf and panicle development. Histological analysis revealed that the elr1 mutant exhibits an increased number of vascular bundles and wider leaves, whereas overexpression of ELR1 result in a decreased number of vascular bundles and narrower leaves. Transcriptome analysis demonstrated that ELR1 may participate in stress response and plant hormone metabolism, particularly cytokinin and jasmonic acid. Chromatin Immunoprecipitation Sequencing (ChIP-seq) results showed that ELR1 targets downstream genes involved in cytokinin metabolism, floral morphogenesis, and sulfated peptide signaling pathways. The expression of cytokinin receptor genes is generally up-regulated in elr1 mutant. Taken together, our results reveal that ELR1 plays an important role and acts as a negative regulator in modulating cytokinin metabolism and signaling pathway.