Science China Life Sciences最新文献

RNA molecules can undergo modification by N-glycans and be displayed on the cell surface. However, recent studies have focused primarily on N-glycan modifications on small RNAs less than 200 nt in length; the transcriptome-wide subtypes of glycosylated RNAs (glycoRNAs) remain poorly characterized. Since glycoRNAs account for only a fraction of the total transcriptome, a validation system for their accurate analysis has not yet been established. In this study, we aimed to comprehensively characterize transcriptome-wide global glycoRNAs and novel glycoRNA subtypes in both epithelial cells and B cells. Using metabolic labeling and density gradient centrifugation methods, we identified glycoRNAs predominantly below 2,000 nt in both epithelial cells and B cells. We then developed the Clier-seq (click chemistry-based enrichment of glycoRNAs sequencing) method to maximize the coverage of glycoRNAs (ranging from 50 to 2,000 nt) and utilized the HISAT-StringTie-Ballgown pipeline to predict novel glycoRNA subtypes. We also established Clier-qPCR assays (click chemistry-based enrichment of glycoRNAs RT-qPCR) to validate the specificity of the candidate glycoRNAs. We demonstrated that transfer RNAs (tRNAs), particularly tRNAs (Ser), tRNAs (Thr), tRNAs (Val), and tRNAs (Lys), are the primary targets of glycosylation. Additionally, we found that vault RNAs (vtRNAs), specifically vtRNA2-1, are glycosylated. Furthermore, we discovered several novel glycosylated long noncoding RNAs ranging from 200 to 400 nt in length. Herein, we propose a standardized bioinformatics pipeline for glycoRNA research, enabling accurate and comprehensive identification of glycoRNAs throughout the transcriptome.

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, notably lacks effective treatment strategies. Although androgen receptor (AR) has emerged as a potential therapeutic target for TNBC, monotherapy with AR inhibitors has proven to be of restricted efficacy. Aiming to develop superior therapeutic approaches, a comprehensive drug library screening was conducted. The ERK inhibitor GDC-0994 exhibited significant synergistic effects with the AR inhibitor bicalutamide. Transcriptome sequencing showed that this combination therapy activates ferroptosis, as evidenced by elevated ROS, increased Fe²⁺ levels, a reduced GSH/GSSG ratio, and lipid peroxide accumulation (MDA and 4-HNE). FOXC2 was identified as a key mediator of this synergy. Specifically, the combination therapy inhibits FOXC2-driven EMT and induces ferroptosis via the FOXC2-Hippo signaling axis, suppressing tumor proliferation, migration, and invasion. In summary, this study uncovers the value of AR/ERK co-targeting in TNBC, which might potentiate the development of novel targeted therapeutic strategies in TNBC.

Histone arginine methylation by protein arginine methyltransferases (PRMTs) is crucial for transcriptional regulation and is implicated in cancers. Despite their therapeutic potential, some PRMTs present challenges as drug targets due to their context-dependent activities. Here, we demonstrate that hypoxia triggers the rapid condensation of PRMT2, which is essential for its histone H3R8 asymmetric dimethylation (H3R8me2a) activity. This process depends on PRMT2's integration into transcriptional condensates, which is mediated by phosphorylation at Serine 12 within its N-terminal intrinsically disordered region. This phosphorylation is critical for hypoxia-inducible gene expression and glioblastoma (GBM) progression. Transcription-associated cyclin-dependent kinases (CDKs), particularly CDK9, drive PRMT2S12 phosphorylation. Inhibition of CDK9 using TG02 suppresses hypoxia-induced H3R8me2a and transcriptional activity. Moreover, the combination of TG02 and temozolomide, the standard chemotherapy for GBM, significantly inhibits tumor progression in mouse xenograft models, an effect partially mediated by targeting PRMT2S12 phosphorylation. Our study uncovers the role of transcriptional condensation in enhancing PRMT activity, reveals a new mechanism for CDK9 inhibitors in modulating context-dependent transcriptional programs, and proposed a combinatorial therapeutic strategy against GBM.

Fibroblast activation plays a critical role in renal fibrosis, the final common pathway of chronic kidney disease (CKD). Previously, we and others reported that yes-associated protein (YAP) is activated in the renal tubular cells of fibrotic kidneys in human patients. However, the mechanisms by which YAP activation in tubular cells contributes to the activities of renal fibroblasts remain unclear. Here, we demonstrate that activation of YAP specifically in renal tubular cells induces E2F transcription factor 2 (E2F2) binding and promotes fibroblast activation through the secretion of fibroblast growth factor 2 (FGF2). FGF2 stimulated the activation of renal interstitial fibroblasts, which exhibited two key characteristics: enhanced synthesis of collagens and fibronectins, which are hallmarks of the fibrotic process, and increased secretion of chemoattractant cytokines that promoted the migration and activation of macrophages. The recruitment and activation of macrophages further exacerbated renal inflammation, thereby accelerating the progression of fibrogenesis. As confirmed by the clinical data, the serum levels of FGF2 were significantly higher in patients with diabetic kidney disease (DKD) and inversely correlated with the estimated glomerular filtration rate. In addition, inhibition of either YAP, E2F2, or FGF2 significantly ameliorated renal fibrosis and improved kidney function in mouse models of chronic kidney disease and renal fibrosis. Our results revealed that YAP complexed with E2F2 and promoted FGF2 expression and secretion in renal tubular cells, which in turn activated fibroblasts, followed by increased macrophage infiltration and activation. The YAP-E2F2-FGF2 axis represents a potential therapeutic target for renal fibrosis.

Cardiovascular disease has been the leading cause of death worldwide for the past 30 years. Recent studies using single cell multiomics analysis have revealed that CD3⁺ T cells are among the most predominant cell types in diseased human cardiac and vascular tissues. Accumulating evidence has demonstrated the critical role of T cells in various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, neonatal heart injuries, autoimmune myocarditis, aortic aneurysm, and diabetic endothelial dysfunction. Recent research has also highlighted the therapeutic potential of CD4⁺ regulatory T (Treg) cells in promoting cardiovascular repair. In this review, we provide a systematic overview of how T cells regulate cardiovascular development, disease progression, and repair. We further discuss current and emerging therapeutic strategies, particularly those targeting Treg cells, aimed at reducing the incidence of cardiovascular events. Finally, we outline key areas for future investigation, including the identification of cardiovascular antigens that trigger T cell activation, the role of T cell aging in cardiovascular disease, and the molecular mechanisms underlying T cell function in the cardiovascular system. A deeper understanding of T cell biology could pave the way for novel, antigen-specific therapeutic interventions to prevent and treat cardiovascular diseases.

Temperature sensation is critical for shaping animal survival strategies and behavioral responses. Animals developed intricate physiological mechanisms to detect ambient temperature due to its profound impact on biological systems. This review consolidates existing research on the molecular mechanisms of animal temperature sensation, focusing on molecular thermosensors, neural pathways, and physiological adaptations, highlighting their evolutionary significance and role in adapting to environmental change. Here, we explore the physiological basis of temperature sensation, including molecular thermosensors and the neural pathways involved in thermoregulation. The ecological significance of temperature sensation is underscored by its influence on species distribution, seasonal behavior, migration patterns, and survival adaptation in climate change. Future research directions could involve a more in-depth exploration of the molecular basis of thermosensation, the functional diversity of thermosensors, and the integration of thermal information. Overall, this review provides a comprehensive overview of the complex interplay between temperature sensation and animal physiology, offering insights into the adaptive strategies of species in the face of environmental challenges.

Maternal fiber intake alters the maternal gut microbiota and metabolites, which benefits offspring health through unclear mechanisms. Using a sow model, the study showed that supplementing with purified fiber (cellulose:guar gum=3:1) increased weaning weight and resistance to LPS-induced intestinal injury. Milk analysis revealed higher levels of immunoglobulins and milk fat. Fecal microbiota transplantation (FMT) from fiber-fed sows to mice replicated these benefits, increasing milk fat, immunoglobulins, and pup growth. Akkermansia muciniphila (AKK) abundance was positively associated with milk quality in both models. Supplementing with AKK mimicked the effects of fiber, boosting milk fat and immunoglobulins. In in vitro experiments with HC11 mammary epithelial cells showed that AKK metabolites enhanced milk fat synthesis and immunoglobulin transporter expression. Metabolite analysis indicated that AKK influences mammary gland function by increasing acetate and propionate levels, with acetate promoting milk fat synthesis via GPR43 and propionate regulating immunoglobulin transport through GPR41. Therefore, maternal fiber intake promotes intestinal AKK abundance, increases short-chain fatty acids (SCFAs) production, and influences lactation via GPR41/43 signaling.