Key Transcription Factor Research Articles

Molecular and Metabolic Regulation of Flavonoid Biosynthesis in Two Varieties of Dendrobium devonianum

Dendrobium devonianum is an important medicinal plant, rich in flavonoid, with various pharmacological activities such as stomachic and antioxidant properties. In this study, we integrated metabolome and transcriptome analyses to reveal metabolite and gene expression profiles of D. devonianum, both green (GDd) and purple-red (RDd) of semi-annual and annual stems. A total of 244 flavonoid metabolites, mainly flavones and flavonols, were identified and annotated. Cyanidin and delphinidin were the major anthocyanidins, with cyanidin-3-O-(6″-O-p-Coumaroyl) glucoside and delphinidin-3-O-(6″-O-p-coumaroyl) glucoside being the highest relative content in the RDd. Differential metabolites were significantly enriched, mainly in flavonoid biosynthesis, anthocyanin biosynthesis, and flavone and flavonol biosynthesis pathways. Transcriptomic analysis revealed that high expression levels of structural genes for flavonoid and anthocyanin biosynthesis were the main reasons for color changes in D. devonianum stems. Based on correlation analysis and weighted gene co-expression network analysis (WGCNA) analysis, CHS2 (chalcone synthase) and UGT77B2 (anthocyanidin 3-O-glucosyltransferase) were identified as important candidate genes involved in stem pigmentation. In addition, key transcription factors (TFs), including three bHLH (bHLH3, bHLH4, bHLH5) and two MYB (MYB1, MYB2), which may be involved in the regulation of flavonoid biosynthesis, were identified. This study provides new perspectives on D. devonianum efficacy components and the Dendrobium flavonoids and stem color regulation.

Maternal high-fat diet orchestrates offspring hepatic cholesterol metabolism via MEF2A hypermethylation-mediated CYP7A1 suppression

BackgroundMaternal overnutrition, prevalent among women of childbearing age, significantly impacts offspring health throughout their lifetime. While DNA methylation of metabolic-related genes mediates the transmission of detrimental effects from maternal high-fat diet (HFD), its role in programming hepatic cholesterol metabolism in offspring, particularly during weaning, remains elusive.MethodsFemale C57BL/6 J mice were administered a HFD or control diet, before and during, gestation and lactation. Hepatic cholesterol metabolism genes in the liver of offspring were evaluated in terms of their expression. The potential regulator of cholesterol metabolism in the offspring’s liver was identified, and the function of the targeted transcription factor was evaluated through in vitro experiments. The methylation level of the target transcription factor was assessed using the MassARRAY EpiTYPER platform. To determine whether transcription factor expression is influenced by DNA methylation, in vitro experiments were performed using 5-azacitidine and Lucia luciferase activity assays.ResultsHere, we demonstrate that maternal HFD results in higher body weight and hypercholesterolemia in the offspring as early as weaning age. Maternal HFD feeding exacerbates hepatic cholesterol accumulation in offspring primarily by inhibiting cholesterol elimination to bile acids, with a significant decrease of hepatic cholesterol 7α-hydroxylase (CYP7A1). RNA-seq analysis identified myocyte enhancer factor 2A (MEF2A) as a key transcription factor in the offspring liver, which was significantly downregulated in offspring of HFD-fed dams. MEF2A knockdown led to CYP7A1 downregulation and lipid accumulation in HepG2 cells, while MEF2A overexpression reversed this effect. Dual luciferase reporter assays confirmed direct modulation of CYP7A1 transcription by MEF2A. Furthermore, the reduced MEF2A expression was attributed to DNA hypermethylation in the Mef2a promoter region. This epigenetic modification manifested as early as the fetal stage.ConclusionsThis study provides novel insights into how maternal HFD orchestrates hepatic cholesterol metabolism via MEF2A hypermethylation-mediated CYP7A1 suppression in offspring at weaning.

Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress.

The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes. SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions. SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA-HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells. Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.

Screening of the key genes and signaling pathways for schizophrenia using bioinformatics and next generation sequencing data analysis

Schizophrenia is thought to be the most prevalent chronic psychiatric disorder. Researchers have identified numerous proteins associated with the occurrence and development of schizophrenia. This study aimed to identify potential core genes and pathways involved in schizophrenia through exhaustive bioinformatics and next generation sequencing (NGS) data analyses using GSE106589 NGS data of neural progenitor cells and neurons obtained from healthy controls and patients with schizophrenia. The NGS data were downloaded from the Gene Expression Omnibus database. NGS data was processed by the DESeq2 package in R software, and the differentially expressed genes (DEGs) were identified. Gene ontology (GO) enrichment analysis and REACTOME pathway enrichment analysis were carried out to identify potential biological functions and pathways of the DEGs. Protein-protein interaction network, module, micro-RNA (miRNA)-hub gene regulatory network, transcription factor (TF)-hub gene regulatory network, and drug-hub gene interaction network analysis were performed to identify the hub genes, miRNA, TFs, and drug molecules. Potential hub genes were analyzed using receiver operating characteristic curves in the R package. In this investigation, an overall 955 DEGs were identified: 478 genes were remarkably upregulated and 477 genes were distinctly downregulated. These genes were enriched for GO terms and pathways mainly involved in the multicellular organismal process, G protein-coupled receptor ligand binding, regulation of cellular processes, and amine ligand-binding receptors. MYC, FN1, CDKN2A, EEF1G, CAV1, ONECUT1, SYK, MAPK13, TFAP2A, and BTK were considered the potential hub genes. The MiRNA-hub gene regulatory network, TF-hub gene regulatory network, and drug-hub gene interaction network were constructed successfully and predicted key miRNAs, TFs, and drug molecules for schizophrenia diagnosis and treatment. On the whole, the findings of this investigation enhance our understanding of the potential molecular mechanisms of schizophrenia and provide potential targets for further investigation.

Transcriptional regulatory network reveals key transcription factors for regulating agronomic traits in soybean

BackgroundTranscription factors (TFs) bind regulatory genomic regions to orchestrate spatio-temporal expression of target genes. Global dissection of the cistrome is critical for elucidating transcriptional networks underlying complex agronomic traits in crops.ResultsHere, we generate a comprehensive genome-wide binding map for 148 TFs using DNA affinity purification sequencing in soybean. We find TF binding sites (TFBSs) exhibit elevated chromatin accessibility and contain more rare alleles than other genomic regions. Intriguingly, the methylation variations at TFBSs partially contribute to expression bias among whole genome duplication paralogs. Furthermore, we construct a soybean gene regulatory network (SoyGRN) by integrating TF-target interactions with diverse datasets encompassing gene expression, TFBS motifs, chromatin accessibility, and evolutionarily conserved regulation. SoyGRN comprises 2.44 million genome-wide interactions among 3188 TFs and 51,665 target genes. We successfully identify key TFs governing seed coat color and oil content and prioritize candidate genes within quantitative trait loci associated with various agronomic traits using SoyGRN. To accelerate utilization of SoyGRN, we develop an interactive webserver (www.soytfbase.cn) for soybean community to explore functional TFs involved in trait regulation.ConclusionsOverall, our study unravels intricate landscape of TF-target interactions in soybean and provides a valuable resource for dissecting key regulators for control of agronomic traits to accelerate soybean improvement.

Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia

Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia.This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.

Transcriptomic and proteomic sequencing unveils the role of vitamin D and metabolic flux shifts in the induction of human hepatic organoids

BackgroundHepatic organoids (HOs), validated through comparative sequencing with human liver tissues, are reliable models for liver research. Comprehensive transcriptomic and proteomic sequencing of HOs throughout their induction period will enhance the platform’s utility, aiding in the elucidation of liver development’s molecular mechanisms.MethodsWe developed hepatic organoids (HOs) from embryonic stem cells (ESCs) through a de novo induction protocol, mimicking the stages of fetal liver development: ESCs to definitive endoderm (DE), then to foregut (FG), hepatoblasts (HB), and finally to HOs stage 1 (HO1), culminating in self-organizing HOs stage 2 (HO2) via dissociation and re-inoculation. The successful establishment of HOs was validated by immunofluorescence staining and RT-qPCR for specific markers. Comprehensive transcriptomic and proteomic sequencing and analysis were conducted on FG, HB, HO1, and HO2.ResultsOur data suggest that several transcription factors (TFs) activated during the HB stage share overlapping target genes with the vitamin D receptor (VDR). Calcitriol, a direct activator of VDR, notably facilitated the FG to HB stage transition by activating VDR and enhancing key TFs, thereby promoting hepatic progenitor cell maturation. Furthermore, our findings revealed a significant transition towards glycolytic energy metabolism at the HO2 stage, characterized by increased glycolytic flux and reduced oxidative phosphorylation. Inhibition of glycolysis using 2-deoxy-D-glucose (2-DG) led to suppressed growth and differentiation at the HO2 stage. Analysis of signaling pathways indicated upregulation of the HIF-1 pathway, which is associated with glycolysis activation, as well as the MAPK and PI3K-AKT pathways, which regulate HIF-1α protein translation.ConclusionsWe elucidated a pivotal role for calcitriol in facilitating the transition from FG to HB by activating VDR and augmenting the expression of critical transcription factors (TFs). Besides, our research underscores a shift in metabolic pathways toward glycolytic energy metabolism in HO2 organoids. Overall, our multiomics approach reveals the intricate molecular regulation during the development of HOs.

Neddylation drives myofibrillogenesis in the developing heart.

Neddylation is a highly conserved post-translational modification that plays critical roles in various cellular processes through the modulation of cullins and non-cullin substrates. While neddylation is known to be essential for embryonic development, tumor growth, and organogenesis of different tissues, its role in cardiogenesis remains unexplored. Here, we investigated the role of neddylation in early cardiac development by deleting the gene encoding a regulatory subunit of the NEDD8-specific E1 activating enzyme, Nae1, globally and in a heart-specific fashion via Nkx2-5Cre. Global deletion of Nae1 in mice led to embryonic lethality before embryonic day (E) 8.5, whereas cardiac-specific NAE1 knockout mice died at around E12.5 with pronounced cardiac effusion and peripheral hemorrhage, characteristic of cardiac failure. Histological analysis revealed significant thinning of the compact myocardium and reduced trabeculae in mutant hearts, which were accompanied by reduced cardiomyocyte proliferation. Unbiased transcriptomic analysis identified perturbations in cardiomyocyte proliferation and myofibril architecture in mutant hearts. Subsequent analysis showed that loss of NAE1 disrupted sarcomere assembly dysregulated the expression of several important contractile proteins, and impaired mitochondrial function in the developing heart, which was accompanied by downregulation of key cardiac transcription factors including NKX2-5 and SRF. Collectively, our findings demonstrate the essential role of neddylation in cardiogenesis at least in part by driving cardiomyocyte proliferation and myofibrillogenesis.

Host Responses to Haustorium Invasion of the Stem Parasitic Plant, Cuscuta campestris, Differ from Responses to Wounding.

The parasitic mechanism employed by the stem parasitic plant, Cuscuta campestris, involves degradation of the host epidermis and intrusion of the cortical tissue of the host stem by a specialized organ called the haustorium. In host plants, the mechanical stimuli associated with this degradation and intrusion of host tissues is considered to be comparable to wounding. However, it has not yet been clarified whether parasitic invasion and wounding induce equivalent responses in host plants. In this study, we demonstrated that parasitic intrusion induced responses that were comparable to wounding in the host plant, Arabidopsis thaliana, including up-regulation of Arabidopsis NAC DOMAIN-CONTAINING PROTEIN 71 (ANAC071), which is a key transcription factor associated with wound repair, cell division, and vascular development. Despite these similarities, we found that the mechanism regulating the induction of cell division- and vascular development-related genes at the host-parasite interface differed from that associated with wound repair. Specifically, ANAC071 was not required for the induction of cell division-related genes, as their upregulation was observed in anac071/096/011 triple mutants as well as in wild-type host plants. We also found that neither auxin nor ethylene plays a significant role in inducing the expression of vascular development-related genes. Thus, the findings show that the mechanisms responsible for upregulating cell division- and vascular development-related genes differ between parasitic and wound repair responses.

Identification of genetic associations between acute myocardial infarction and non-small cell lung cancer

IntroductionA growing body of evidence suggests a potential connection between myocardial infarction (MI) and lung cancer (LC). However, the underlying pathogenesis and molecular mechanisms remain unclear. This research aims to identify common genes and pathways between MI and LC through bioinformatics analysis.MethodsTwo public datasets (GSE166780 and GSE8569) were analyzed to identify differentially expressed genes (DEGs). Common DEGs were enriched using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Hub genes were identified and their diagnostic performance was evaluated. Gene co-expression networks, as well as regulatory networks involving miRNA-hub genes and TF-hub genes, were also constructed. Finally, candidate drugs were predicted.ResultsAmong the datasets, 34 common trend DEGs were identified. Enrichment analysis linked these DEGs to key biological processes, cellular components, and molecular functions. Eight hub genes (CEBPA, TGFBR2, EZH2, JUNB, JUN, FOS, PLAU, COL1A1) were identified, demonstrating promising diagnostic accuracy. Key transcription factors associated with these hub genes include SP1, ESR1, CREB1, ETS1, NFKB1, and RELA, while key miRNAs include hsa-mir-101-3p, hsa-mir-124-3p, hsa-mir-29c-3p, hsa-mir-93-5p, and hsa-mir-155-5p. Additionally, potential therapeutic drugs were identified, with zoledronic acid anhydrous showing potential value in reducing the co-occurrence of the two diseases.DiscussionThis study identified eight common signature genes shared between NSCLC and AMI. Validation datasets confirmed the diagnostic value of key hub genes COL1A1 and PLAU. These findings suggest that shared hub genes may serve as novel therapeutic targets for patients with both diseases. Ten candidate drugs were predicted, with zoledronic acid showing potential for targeting dual hub genes, offering a promising therapeutic approach for the comorbidity of lung cancer and myocardial infarction.

The pivotal role of the Hes1/Piezo1 pathway in the pathophysiology of glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA-seq revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved the lacuno-canalicular network and reduced sclerostin production and the receptor activator of NF-κB/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechanostimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteum-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.

Chitosan nanoparticles loaded with metformin and digoxin synergistically inhibit MCF-7 breast cancer cells through suppression of NOTCH-1 and HIF-1α gene expression

This study investigated the potential anticancer efficacy of co-treating the MCF-7 breast cancer cell line with chitosan nanoparticles (Cs NPs) loaded with metformin (Met) and digoxin (Dig). The Cs NPs had a size range of 90.6–148.7 nm and a zeta potential of +11.7 to +11.9 mV, indicating a positive surface charge. Notably, the Cs NPs demonstrated high encapsulation efficiencies, with values of 90.97 ± 5.14 % for Met and 92.12 ± 3.81 % for Dig, indicating effective loading of both drugs. The results revealed that the co-delivery of Met and Dig via Cs NPs significantly enhanced the anticancer efficacy, outperforming the treatment with individual free drugs or their combination, thereby demonstrating the potential benefits of nanoparticle-mediated co-administration. The drugs-loaded Cs NPs induced a marked increase in apoptosis in MCF-7 cells, with a cell death rate of 67.56 %, and significantly reduced mammosphere size by 48.08 %, thereby demonstrating a superior therapeutic efficacy compared to treatment with individual free drugs or their combination. Notably, the drug-loaded Cs NPs exhibited potent anti-migratory and anti-angiogenic effects, significantly inhibiting cell migration and new blood vessel formation, which may contribute to overcoming the inherent resistance of tumors to conventional therapies. Mechanistically, the co-treatment with drugs-loaded Cs NPs was found to downregulate the expression of NOTCH-1 and HIF-1α, two key transcription factors involved in tumor cell survival and adaptation, suggesting that their inhibition is a crucial component of the therapeutic efficacy of this treatment strategy. Collectively, the findings of this study suggest that the co-delivery of Met and Dig via chitosan Cs NPs represents a promising therapeutic strategy for breast cancer, as it effectively targets key pathways involved in tumor growth and progression, and underscores the potential of Cs NPs as a versatile platform for cancer therapy.

BRAFV600E induces key features of LCH in iPSCs with cell type-specific phenotypes and drug responses.

Langerhans cell histiocytosis (LCH) is a clonal hematopoietic disorder defined by tumorous lesions containing CD1a+/CD207+ cells. Two severe complications of LCH are systemic hyperinflammation and progressive neurodegeneration. The scarcity of primary samples and lack of appropriate models limit our mechanistic understanding of LCH pathogenesis and affect patient care. We generated a human in vitro model for LCH using induced pluripotent stem cells (iPSCs) harboring the BRAFV600E mutation, the most common genetic driver of LCH. We show that BRAFV600E/WT iPSCs display myelo-monocytic skewing during hematopoiesis and spontaneously differentiate into CD1a+/CD207+ cells that are similar to lesional LCH cells and are derived from a CD14+ progenitor. We show that BRAFV600E modulates the expression of key transcription factors regulating monocytic differentiation and leads to an upregulation of pro-inflammatory molecules and LCH marker genes early during myeloid differentiation. In vitro drug testing revealed that BRAFV600E-induced transcriptomic changes are reverted upon treatment with MAPK-pathway inhibitors (MAPKi). Importantly, MAPKi do not affect myeloid progenitors but reduces only the mature CD14+ cell population. Furthermore, iPSC-derived neurons (iNeurons) co-cultured with BRAFV600E/WT iPSC-derived microglia-like cells (iMGL), differentiated from iPSC-derived CD34+ progenitors, exhibit signs of neurodegeneration with neuronal damage and release of neurofilament light chain. In summary, the iPSC-based model described here provides a platform to investigate the effects of BRAFV600E in different hematopoietic cell types and provides a tool to compare and identify novel approaches for the treatment of BRAFV600E-driven diseases.

Adaptations of Rice Seed Germination to Drought and Hypoxic Conditions: Molecular and Physiological Insights

Seed germination is crucial for plant survival, crop stand establishment, and achieving optimal grain yield. The main objective of this review is to explore the physiological and molecular mechanisms governing rice seed germination under aerobic (water stress) and anaerobic (hypoxic) conditions in direct-seeded rice (DSR) systems. Moreover, it discusses the recent genomic advancements and innovations to improve rice seed germination. Here, we discuss how coleoptile and mesocotyl elongation plays a vital role in anaerobic germination (AG) and the function of raised antioxidants, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in maintaining Reactive Oxygen Species (ROS), and malondialdehyde (MDA) homeostasis for stabilizing seed germination in water-scarce conditions. This study comprehensively highlights the functions and dynamics of phytohormones—GA (gibberellic acid) and ABA (abscisic acid)—key regulatory genes, transcription factors (TFs), key proteins, and regulatory metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid cycle (TCA), in regulating seed germination under both conditions. Conventional agronomic and cultural practices, such as seed selection, seed priming, seed coating, and hardening, have proven to improve seed germination. Moreover, the utilization of molecular and novel approaches—such as clustered regularly interspaced short palindromic repeat (CRISPR-Cas9) mediated genome editing, marker-assisted selection (MAS), genome-wide associations studies (GWAS), single nucleotide polymorphisms (SNPs), multi-omics, RNA sequencing—combined with beneficial quantitative trait loci (QTLs) has expanded knowledge of crop genomics and inheritance. These advancements aid the development of specific traits for enhancing seed germination in DSR.

Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic analysis across T cell subsets by integrating single-cell RNA-seq, RNA-seq, and ATAC-seq and further analyzed CD8+ T cell subpopulations following symptom provocation. Specific subsets of CD8+ T cells, as well as certain innate T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated factors. Together, these data identify T cell exhaustion as a component of ME, a finding which may provide a basis for future therapies, such as checkpoint blockade, metabolic interventions, or drugs that target chronic viral infections.

CsCBF1/CsZHD9‐CsMADS27, a critical gene module controlling dormancy and bud break in tea plants

SUMMARYTea plants are perennial evergreen woody crops that originated in low latitudes but have spread to high latitudes. Bud dormancy is an important adaptation mechanism to low temperatures, and its timing is economically significant for tea production. However, the core molecular networks regulating dormancy and bud break in tea plants remain unclear. In the present study, a MADS‐box transcription factor CsMADS27 was identified in tea plants. Gene and phenotype characterizations following ectopic overexpression and endogenous silencing experiments are consistent with a role for CsMADS27 in dormancy and sprouting in different tea cultivars. Furthermore, CsDJC23 was found to be a downstream target of CsMADS27 and implicated in bud sprouting. Based on yeast one‐hybrid screening and comprehensive verification, CsCBF1 and CsZHD9 were identified as upstream transcriptional inhibitors and activators of CsMADS27, respectively, with the two proteins showing direct interactions and competitive binding effects. Histone acetylation (H3K27Ac) in the first exon and intron regions of CsMADS27 was associated with a positive role in CsMADS27 expression. These results revealed that CsMADS27 is a key transcription factor involved in the regulation of dormancy and bud break. Furthermore, the CsCBF1/CsZHD9‐CsMADS27 module plays a critical role in sensing environmental factors and accurately regulating the growth and development of overwintering buds in tea plants.

Mechanism of Action and Related Natural Regulators of Nrf2 in Nonalcoholic Fatty Liver Disease.

With the acceleration of people's pace of life, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, which greatly threatens people's health and safety. Therefore, there is still an urgent need for higher-quality research and treatment in this area. Nuclear factor Red-2-related factor 2 (Nrf2), as a key transcription factor in the regulation of oxidative stress, plays an important role in inducing the body's antioxidant response. Although there are no approved drugs targeting Nrf2 to treat NAFLD so far, it is still of great significance to target Nrf2 to alleviate NAFLD. In recent years, studies have reported that many natural products treat NAFLD by acting on Nrf2 or Nrf2 pathways. This article reviews the role of Nrf2 in the pathogenesis of NAFLD and summarizes the currently reported natural products targeting Nrf2 or Nrf2 pathway for the treatment of NAFLD, which provides new ideas for the development of new NAFLD-related drugs.

The mechanism of DEHP-induced lipid accumulation in liver of female zebrafish

Diethylhexyl phthalate (DEHP) is a typical environmental pollutant and poses a potential threat to organisms by disrupting the lipid metabolism. This study found that DEHP at environmental concentrations, led to lipid accumulation in female zebrafish, as indicated by significant increases in the content of total cholesterol, triglycerides and the lipid droplets, in a concentration-dependent manner. However, how DEHP induces the lipid accumulation remains poorly understood. Our results demonstrated that DEHP up-regulated the expression of fat synthesis related-genes fas, acc, acs, elvol6, scd and dgat1, and increased the enzymatic activity of fatty acid synthase and acetyl-CoA carboxylase. Furthermore, the expression of several key transcription factors that regulate fat synthesis was detected, among which active sterol regulatory element-binding protein-1 (SREBP-1) was significantly increased. When active SREBP-1 was inhibited with specific inhibitor or knocked down by transient transfection, the expression of lipid synthesis-related genes was significantly decreased in DEHP group, indicating that DEHP disrupted the lipid synthesis via SREBP-1 pathway. Additionally, molecular docking revealed direct interaction sites between DEHP and SREBP-1. Our findings revealed that DEHP could directly activate SREBP-1-mediated lipid synthesis, providing theoretical basis for DEHP threatening biological health.

Danhong Injection Modulates Microglial Polarization and Neuroinflammation via the JUNB/NF-κB Pathway in Ischemic Stroke.

Ischemic stroke (IS) is a leading cause of death and disability in China. Danhong Injection (DHI) is a traditional Chinese medicine preparation made from Salvia miltiorrhiza var. miltiorrhiza and Carthamus tinctorius L. It is used for treating stroke in China with proven safety and efficacy. Microglia M1/M2 polarization is a key factor in IS inflammatory response. However, the key transcription factors that regulate microglia polarisation are unknown. It is also not clear how DHI exerts its mechanism in the treatment of IS. This research aimed to investigate the effect of DHI on microglial polarization and neuroinflammation associated with IS and to elucidate the underlying mechanisms, with an emphasis on the JUNB/NF-κB signaling pathway. An oxygen-glucose deprivation (OGD) damage cell model and a permanent middle cerebral artery occlusion (pMCAO) model in C57BL/6 mice were employed. Neurological deficits, cerebral infarct volume, and microglial activation were assessed. Non-targeted metabolomics analysis with UHPLC-QE-MS and molecular biology methods, including RT-qPCR and Western blot, were applied to investigate the mechanisms. In vivo, DHI decreased inflammation, reduced brain damage, and enhanced neurological function. DHI also ameliorated microglial activation and OGD-induced apoptosis in vitro. Metabolomics analysis identified significant metabolic changes, particularly in amino acid metabolism. Additionally, DHI treatment decreased the upregulated mRNA levels of ASS1 and ASL after OGD, indicating an influence on the arginine biosynthesis pathway, which is crucial for microglial function. DHI modulated the M1 to M2 phenotypes of microglial polarization and regulated microglial polarization through the JUNB/NF-κB signaling pathway. This was confirmed by JUNB silencing experiments. DHI exhibits neuroprotective effects via suppressing ASS1 through the JUNB/NF-κB pathway, promoting the M2 state of microglia, and lowering the expression of inflammatory cytokines. This research unveils the potential therapeutic target of JUNB for IS treatment and sheds light on the novel intervention mechanism of DHI in microglial cells.

Unveiling the potential: implications of successful somatic cell-to-ganglion organoid reprogramming.

Organoids have a wide range of potential applications in areas such as organ development, precision medicine, regenerative medicine, drug screening, disease modeling, and gene editing. Currently, most organoids are generated through three-dimensional (3D) in vitro culture of adult stem cells or pluripotent stem cells. However, this method of generating organoids still has several limitations and challenges, including complex manipulations, costly culturing materials, extended time requirements, and certain heterogeneity. Recently, we have found that fibroblasts, when overexpressing several key regulatory transcription factors, are able to directly and rapidly generate two types of ganglion organoids: sensory ganglion (SG) and autonomic ganglion (AG) organoids. They have structures and electrophysiological properties similar to those of endogenous organs in the body. Here, we provide a brief overview of organoid development, focusing on direct reprogramming of SG and AG organoids and their transplantation and regeneration. Finally, the advantages and prospects of direct reprogramming of organoids are discussed.