GEO 数据集

主题由标题与摘要自动归类；样本量为数据集标注之和，SuperSeries 可能与其 SubSeries 重复计算。

• TAF1-dependent transcriptional dysregulation underlies multiple sclerosis
  GSE255578Mus musculus12 个样本2026-10-31

  In the search for new targets for therapeutic intervention, MS-associated common variants provide clues about etiology-relevant molecular mechanisms, but the individual effect of each variant is minimal. A current priority to better understand the molecular basis of MS and to identify targets for designing progression-modifying therapies, is therefore to detect in the CNS of MS patients specific biochemical alterations -likely related to environmental factors and/or GWAS-identified molecular mechanisms- that per se would suffice to cause MS progression.
• Deciphering the interaction between Twist1 and PPARγ during adipocyte differentiation
  GSE246718Mus musculus12 个样本2026-10-31

  Obesity, a worldwide epidemic in recent years, is mainly due to the uncontrolled development of adipose tissues, which includes adipocyte hypertrophy and hyperplasia. Adipocyte differentiation is a process involving multiple transcription factor cascades, and the exact mechanism has not yet been defined. As a bHLH transcription factor, Twist1 exerts its activity by forming homo- or heterodimers with other factors. In this study, we showed Twist1 restricts adipogenesis through PPARγ. Expression of various differentiation markers (including PPARγ and adiponectin) and triglyceride-containing lipid droplets were decreased with overexpression of Twist1. Pathway enrichment analysis of RNA-seq data showed that differentially expressed genes (DEGs) caused by Twist1 overexpression were significantly related to lipolysis and PPARγ signaling. This implicates that Twist1 plays important regulatory roles in these processes. ChIP and dual luciferase assays showed that Twist1 could bind either PPARγ or adiponectin promoter to repress their respective transcription or directly to PPARγ protein to regulate its transcriptional activity. Furthermore, Twist1 directly interacted RXRα, which usually forms heterodimer with PPARγ to regulate adipogenesis. Taken together, our results suggest that Twist1 is an inhibitory modulator of adipogenesis and its function is likely through direct interaction with PPARγ protein or its gene promoter.
• The metabolic reprogramming of T cells controls airway remodeling in severe asthma
  GSE352552Mus musculus10 个样本2026-10-30

  Background: Mixed granulocytic asthma (MGA) is a severe Th2-low endotype, characterized by high Th17/neutrophilic burden and exacerbated airway remodeling. Both features confer resistance to inhaled corticosteroids and typical asthma treatments. Objective: We aimed to address gaps in knowledge, including how Th17 cells induce pathological tissue remodeling and how Th17 differentiation occurs in response to allergens. Methods: We generated a Th2-low murine model of asthma on the Il4rα-/- background that mimics the decrease in type 2 response seen in corticosteroid-resistant patients. We monitored major features of human disease including heightened airway reactivity to methacholine, Th17/neutrophilic inflammation, airway remodeling, and resistance to corticosteroid treatment. Comparative transfer of Th2 versus Th17 cells were analyzed. We further investigated how the mitochondrial oxidative phosphorylation (OXPHOS) pathway modulates pathogenic Th17 cell reprogramming by in vitro T cell cultures and in vivo therapeutic blockades. Results: LIGHT (aka TNFSF14) and the OXPHOS pathway are enriched in human MGA and likewise upregulated in this mouse model. We show OXPHOS promotes the metabolic reprograming of Th17 cells, to sustain their survival despite steroid treatment and produce LIGHT that controls airway remodeling. Mechanistically, OXPHOS regulates RORγt expression and the subsequent transcriptional network to program differentiation of Th17 cells, whereas LIGHT drives airway remodeling by activating the MMP9-dependent TGFβ pathway. Additionally, OXPHOS+Th17 cells promote the expression of osteopontin necessary for fibroblast activation. LIGHT antagonistic blockade reduces airway remodeling, whereas OXPHOS inhibition kills Th17 cells and subsequent neutrophilia. Importantly, the dual blockade of LIGHT and OXPHOS reverses all features of MGA back to baseline and reciprocally increases the numbers of Treg cells. Conclusions: The dual blockade of LIGHT and OXPHOS constitutes a promising target for clinical interventions in human MGA, possibly extending to other Th17-driven fibrotic diseases.
• A CD4-lineage erythro-myeloid progenitor within the adult bone marrow defines an alternative pathway for macrophage generation [RNA-Seq]
  GSE345263Mus musculus10 个样本2026-10-30

  Tissue-resident macrophages originate from distinct developmental sources, but in adulthood, their replenishment is thought to depend exclusively on circulating monocytes. Here, we identify a previously unrecognized CD4-lineage erythro-myeloid progenitor, termed EMPROR (Erythro-Myeloid Progenitor), that resides in the adult bone marrow and defines an alternative pathway for generating macrophages. EMPROR cells are phenotypically and transcriptionally distinct from hematopoietic stem cells, common myeloid progenitors, and monocyte precursors. They lack expression of Csf1r and Ccr2 while expressing Cd4 and c-Kit. Single-cell RNA sequencing, RNA velocity analysis, and in vitro and in vivo lineage assays demonstrate a multilineage potential encompassing macrophage, neutrophil, megakaryocytic, and erythroid fates. In vivo, EMPROR cells efficiently generate perivascular and tumor-associated macrophages independently of CCR2-mediated monocyte recruitment, and also contribute to erythroid and granulocytic lineages under inflammatory and neoplastic conditions. Transcriptomic comparisons position EMPROR cells closest to embryonic erythro-myeloid progenitors, indicating that an embryonic-like erythro-myeloid program persists within the adult bone marrow. These findings expand current models of adult myelopoiesis and highlight a previously unappreciated developmental pathway that sustains macrophage diversity beyond the classical monocyte lineage.

  单细胞
• A CD4-lineage erythro-myeloid progenitor within the adult bone marrow defines an alternative pathway for macrophage generation
  GSE345108Mus musculus12 个样本2026-10-30

  Tissue-resident macrophages originate from distinct developmental sources, but in adulthood, their replenishment is thought to depend exclusively on circulating monocytes. Here, we identify a previously unrecognized CD4-lineage erythro-myeloid progenitor, termed EMPROR (Erythro-Myeloid Progenitor), that resides in the adult bone marrow and defines an alternative pathway for generating macrophages. EMPROR cells are phenotypically and transcriptionally distinct from hematopoietic stem cells, common myeloid progenitors, and monocyte precursors. They lack expression of Csf1r and Ccr2 while expressing Cd4 and c-Kit. Single-cell RNA sequencing, RNA velocity analysis, and in vitro and in vivo lineage assays demonstrate a multilineage potential encompassing macrophage, neutrophil, megakaryocytic, and erythroid fates. In vivo, EMPROR cells efficiently generate perivascular and tumor-associated macrophages independently of CCR2-mediated monocyte recruitment, and also contribute to erythroid and granulocytic lineages under inflammatory and neoplastic conditions. Transcriptomic comparisons position EMPROR cells closest to embryonic erythro-myeloid progenitors, indicating that an embryonic-like erythro-myeloid program persists within the adult bone marrow. These findings expand current models of adult myelopoiesis and highlight a previously unappreciated developmental pathway that sustains macrophage diversity beyond the classical monocyte lineage.

  单细胞
• Transcriptional response of J774A.1 macrophages to a monoacylglycerol mixture, oleic acid, or palmitic acid
  GSE345076Mus musculus24 个样本2026-10-30

  Monoacylglycerols (MAGs) accumulate in adipose tissue macrophages, but whether macrophages respond to MAGs differently than to free fatty acids is not established. To determine the concentration at which murine J774A.1 macrophages mount a transcriptional response to these lipids, cells were treated for 24 h with a commercial monoacylglycerol mixture, oleic acid, or palmitic acid at 500 uM or 5 mM and profiled by bulk RNA sequencing. At 5 mM, the MAG mixture altered a small set of genes that changed concordantly with oleic acid and included the lipid droplet protein Plin2 and the fatty acid oxidation gene Cpt1a, whereas palmitic acid induced inflammatory transcripts including Il1b and Trem1 with essentially no overlap with the MAG mixture. These data indicate that monoacylglycerols in this mixture engage a lipid handling program rather than an inflammatory one in macrophages.
• The pyrin inflammasome senses OCTN2-mediated uptake of extracellular ʟ-carnitine from muscle injury or ingestion
  GSE343742Mus musculus12 个样本2026-10-30

  Red-meat-containing diets are epidemiologically associated with diseases of chronic inflammation, while diets that restrict red meat improve health. Yet, it is uncertain how red meat incites inflammation. Here, we discover that ʟ-carnitine, an amino acid highly concentrated in skeletal muscle myocytes, drives inflammasome activation in lipopolysaccharide (LPS)-challenged mice and LPS-primed murine and human macrophages. We find that extracellular ʟ-carnitine represses mevalonate synthesis, thereby triggering activation of the pyrin inflammasome, downstream of cellular import by the high-affinity ʟ-carnitine transporter OCTN2. We find that the inflammatory response to skeletal muscle injury also requires pyrin and OCTN2. Thus, in summary, we identify macrophages as sentinels of exogenous and endogenous extracellular ʟ-carnitine that serve as a proxy for skeletal myocyte damage, and we open the field to examine the mechanistic basis for how excess dietary intake of carnitine-rich food drives inflammatory disease.
• FGF12 and FGF13 promote atrial rhythm homeostasis
  GSE334673Mus musculus16 个样本2026-10-30

  Data from human and mouse studies of atrial fibrillation implicate FGF12/13 in atrial fibrillation. To determine if FGF12 and FGF13 regulate atrial rhythm homeostasis, we inactivated them in mouse aCMs. Serial EKG analysis revealed that dual Fgf12/13 inactivation results in AF.
• Lidocaine attenuates LPS-induced macrophage inflammation through transcriptomic reprogramming and inhibition of NF-κB/STAT1 signaling
  GSE329186Mus musculus12 个样本2026-10-30

  Lidocaine has been increasingly recognized for its anti-inflammatory and immunomodulatory properties, but the global transcriptional mechanisms remain unclear. In this study, RAW264.7 macrophages were stimulated with lipopolysaccharide (LPS) and treated with lidocaine at different concentrations. RNA sequencing was performed to characterize transcriptomic alterations induced by lidocaine. Lidocaine significantly reduced LPS-induced secretion of TNF-α and IL-6, partially reversed inflammatory gene expression programs, and suppressed multiple inflammation-related pathways, including TNFα signaling via NF-κB, interferon responses, inflammatory response, and IL6/JAK/STAT signaling. Further validation confirmed reduced expression of Il6, Tnf, Il1b, and Nos2, inhibition of p65 and STAT1 phosphorylation, and downregulation of iNOS. These findings demonstrate that lidocaine attenuates macrophage inflammatory responses through coordinated transcriptional reprogramming and suppression of NF-κB/STAT1 signaling.
• T cell-derived IL-17A deteriorates periodontium under insulin resistance
  GSE327375Mus musculus12 个样本2026-10-30

  Insulin resistance (IR) is a systemic metabolic disorder associated with chronic inflammatory diseases, yet the immune-molecular mechanisms by which IR exacerbates periodontitis remain elusive. This study aimed to investigate the role of T cell-derived interleukin (IL) -17A in IR-aggravated periodontitis and the underlying mechanisms. A total of 4948 participants aged ≥30 years from the National Health and Nutrition Examination Survey 2009–2014 were included to assess the clinical association between IR and periodontitis. A murine model of IR combined with periodontitis was established. Il17a⁻/⁻ mice and FTY720 were used to verify the function of IL-17A and CD4⁺ T cell migration. Bulk RNA sequencing, flow cytometry, immunofluorescence, micro-computed tomography (micro-CT), and histological staining were performed to characterize immune cell infiltration and periodontium destruction. Primary mouse gingival fibroblasts (GFs) were isolated to explore the effects of IL-17A on inflammatory responses and collagen metabolism. The results demonstrated that IR was an independent risk factor for periodontitis at the population level (Odds Ratio=1.22, 95% CI 1.06–1.41) and significantly exacerbated alveolar bone loss and collagen degradation in the mouse model. IR-aggravated periodontitis was accompanied by increased gingival infiltration of CD4⁺ T cells and elevated IL-17A expression, with IL-17A primarily secreted by cervical lymph node-derived CD4⁺ T cells. Il17a⁻/⁻ and FTY720 treatment alleviated periodontium destruction and reduced gingival immune cell infiltration. Furthermore, the recombinant IL-17A upregulated the expression of pro-inflammatory genes (Il6, Il1β, Tnfa) and the collagen-degrading enzyme gene Mmp3, downregulated the collagen synthesis gene Col1a1, and inhibited the migration of GFs via the NF-κB signalling pathway. In conclusion, IL-17A secreted by cervical lymph node-derived CD4⁺ T cells promotes IR-aggravated periodontium destruction, by regulating the periodontal immune microenvironment and modulating GFs function. These findings identified IL-17A as a potential therapeutic target for periodontitis in patients with IR.
• NFYA regulates spermatogenesis through multifaceted chromatin interactions
  GSE326586Mus musculus22 个样本2026-10-30

  During spermatogenesis, germ cells undergo extensive chromatin remodeling to promote highly diverse and stage-specific transcriptional programs that drive differentiation, meiosis, and spermiogenesis. However, conventional loss-of-function approaches do not allow systematic interrogation of gene function across spermatogenesis in vivo. Here, we introduce a protein-degron strategy coupled with intra-seminiferous tubule injection (dTAG-IS) to enable rapid, simultaneous, and stage-resolved functional investigation of NFYA during spermatogenesis. Acute NFYA-depletion induces apoptosis in differentiating spermatogonia (diff-Spg), pachytene spermatocytes (pSpc), and round spermatids (rStd), revealing an essential requirement across spermatogenesis. Mechanistically, NFYA exhibits stage-specific chromatin-binding patterns and directly regulates distinct transcriptional programs, including cell cycle progression and histone assembly in diff-Spg; chromosome organization and DNA damage response in pSpc; and antioxidative stress programs in rStd. Together, our study underscores dTAG-IS as a versatile strategy for in vivo loss-of-function studies during spermatogenesis and establishes NFYA as a multifaceted regulator that drives stage-specific transcriptional programs to ensure spermatogenesis progression.
• Tissue Nano-Transfection Promotes Vascularization to Enhance Acellular Nerve Allograft–Mediated Nerve Repair [RNAseq_invitro_ANAs]
  GSE324287Mus musculus16 个样本2026-10-30

  Peripheral nerves possess an inherent capacity for regeneration, yet functional recovery following an injury remains inconsistent despite advances in microsurgical repair. Autologous nerve grafts are the gold standard for complex peripheral nerve injuries (PNI) but are constrained by limited donor availability, donor-site morbidity, and size mismatches. Acellular nerve allografts (ANAs) offer off-the-shelf availability and can bridge longer defects, but their performance is hindered by the lack of intrinsic Schwann cells and vascular structures, essential for axonal regeneration. Here, we report on the use of Tissue Nanotransfection (TNT), a novel non-viral platform that allows the delivery of nucleic acids into solid tissues in combination with ANAs. We used TNT to reprogram resident nerve cells toward a vasculogenic phenotype to locally increase vascularization and improve outcomes following PNI reconstruction. We show that vasculogenic transcription factors (Etv2, Fli1, and Foxc2; EFF) drive transcriptomic changes in vitro. In vivo, vasculogenic TNT increases the number of endothelial cells within ANAs as early as 5 weeks post-treatment. Mice receiving ANAs combined with vasculogenic TNT exhibited superior functional recovery, including enhanced muscle strength and progressive restoration outperforming ANAs only controls. Region-specific transcriptomics reveal that the site of the TNT application along the host nerve critically influences the regenerative response. Together, these findings identify vasculogenic TNT as a potent, non-viral strategy to enhance ANA-mediated repair by promoting localized vasculogenesis and supporting improved functional recovery and muscle protection.
• CAR-DC1s drive polyclonal neoantigen-specific immunity
  GSE319838Mus musculus16 个样本2026-10-30

  CAR therapies typically target single antigens, limiting recognition and favoring tumour escape. Conversely, type 1 conventional dendritic cells (DC1s) are specialized to cross-prime diverse T-cell responses, but lack the pathogen-derived signals required for strong activation in "self"-derived tumors. Efforts to hard-wire such signals using CARs in DC1s have remained elusive, in part due to a lineage-specific constraint on stable, high-level CAR surface expression. Here, we show that replacing conventional antibody fragments with single-domain nanobodies overcomes this DC1–specific constraint and enables construction of tumour-targeted receptors with high surface density. By systematically optimizing TLR4-derived elements within this scaffold, we developed a receptor that couples tumor engagement to TLR signaling, markedly enhancing activation, capture and cross-presentation of endogenous antigens. In a heterogeneous syngeneic sarcoma model, CAR-DC1s induce complete tumor rejection and durable memory. Integrating mass spectrometry of the cross-presented tumour immunopeptidome with tetramer staining, single-cell RNA sequencing paired with TCR sequencing, and adoptive transfer, we show that CAR-DC1s imprint a stem-like transcriptional programme on newly primed T-cells and expand a polyclonal, recall-competent tumour-specific repertoire, thereby reprogramming the quality and breadth of anti-tumour immunity against endogenous neoantigen in vivo.

  单细胞
• Ribosomal modification by BUD23 drives selective translational control over energy state and metabolic health
  GSE308207Mus musculus16 个样本2026-10-30

  Efficient energy metabolism is essential for health, and its dysregulation drives conditions like cardiometabolic disease and obesity. Delivery of regulatory control through translation and ribosome function is emerging as important. Here, we identify the rRNA methyltransferase BUD23 as a potent regulator of cellular and systemic energy homeostasis. Adipocyte-specific deletion of BUD23 in mice regulates lipid and mitochondrial metabolism resulting in a pronounced lean phenotype and resistance to diet-induced obesity. Mechanistically, BUD23 modulates translation initiation and efficiency of mRNAs with specific features – including short 5’ UTR length and GC-rich post-initiation codon usage - characteristic of mitochondrial and lipogenic proteins. Human genetic analyses and drug-target Mendelian Randomisation support a role for BUD23 in cardiometabolic traits and diseases. Together, our findings uncover a conserved translational control mechanism that regulates energy metabolism and offers a potential therapeutic target.
• LAMA2-related muscular dystrophy alters Schwann cell calcium homeostasis and increases peripheral nerve inflammation
  GSE351764Mus musculus43 个样本2026-10-29

  LAMA2-related muscular dystrophy (LAMA2-RD) affects skeletal muscle and peripheral nerves, yet the consequences of LAMA2 deficiency for peripheral nerve integrity beyond early postnatal development remain incompletely understood. We investigated sciatic nerve architecture and molecular alterations across postnatal life in hypomorphic Lama2dy2J/dy2J mice. LAMA2 localizes around the abaxonal surface of myelinating Schwann cells in control nerves. LAMA2-deficient nerves exhibited patchy regions lacking myelinated axons from early postnatal stages into adulthood, including expanded Remak bundles along with axons completely lacking normal Schwann cell ensheathment. In adult nerves, myelin infolding and reduced myelin circularity revealed abnormalities in the architecture of myelin that had formed. Bulk sciatic nerve RNA sequencing identified altered calcium-signaling and immune-related transcriptional signatures. Complementary Fura Red measurements in primary nerve-derived Schwann cell cultures demonstrated decreased intracellular calcium in LAMA2-deficient samples, while ATP-evoked responses were preserved. Older LAMA2-deficient nerves also exhibited increased CD45+CD11b+ myeloid-cell infiltration. Together, these observations extend the characterization of LAMA2-associated neuropathy into adulthood and identify calcium homeostasis and neuroimmune responses as candidate processes relevant to persistent peripheral nerve pathology.
• Mitochondrial Complex III Drives Skeletal Muscle Metabolic Reprogramming and Alters Glucose Utilization
  GSE347652Mus musculus12 个样本2026-10-29

  Mitochondrial dysfunction is closely associated with metabolic disease, yet how mitochondrial respiratory capacity influences skeletal muscle glucose handling remains poorly understood. Here, we investigate the role of mitochondrial Complex III in skeletal muscle using a muscle-specific Rieske iron-sulfur protein (RISP) knockout model. Loss of RISP did not impair basal Complex III respiratory capacity, but reduced skeletal muscle endurance while preserving muscle contractility and overall muscle structure. Importantly, Complex III deficiency was accompanied by alterations in systemic glucose metabolism. RISP-deficient mice exhibited lower basal glucose levels in fed and fasted states and improved glucose tolerance. Together, these findings suggest that impaired Complex III function triggers metabolic adaptations that extend beyond mitochondrial respiration and influence whole-body glucose handling. These findings identify mitochondrial Complex III as a potential metabolic checkpoint linking skeletal muscle oxidative capacity with glucose utilization and systemic glucose homeostasis. This work raises the possibility that enhancing skeletal muscle glucose utilization could represent a strategy to reduce glucose stress in metabolic disease, including diabetes.
• Lamin B1 physically regulates neuronal migration by modulating nuclear deformability in the developing cortex
  GSE347519Mus musculus18 个样本2026-10-29

  Neuronal migration positions billions of neurons to form a functional brain. Effective navigation through the cortex requires precise regulation of nuclear mechanics in migrating neurons. We demonstrate that Lamin B1 (LB1) regulates neuronal migration by modulating nuclear deformability. Elevated LB1 in neurons halted migration in vivo, without affecting laminar identity or pre-migratory gene expression. Mispositioned neurons subsequently caused electrophysiological defects in the brain. In vitro, increased LB1 raised nuclear stiffness, as measured by atomic force microscopy, and reduced neuronal motility in confined environments reconstituted with microchambers. Computational modeling predicted a temporal link between nuclear deformation and increased migration velocity, which was validated experimentally through live imaging. Notably, cerebral organoid assays using induced pluripotent stem cells established from patients with LMNB1 duplication exhibited impaired neuronal migration in a human model. Collectively, these findings establish LB1 as a critical regulator of nuclear mechanics, ensuring accurate spatiotemporal positioning of neurons.

  计算与 AI
• Acquired resistance to anti-PD-1 therapy is associated with tumor intrinsic macrophage reprogramming.
  GSE344292Mus musculus19 个样本2026-10-29

  Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis can produce durable tumor responses, but acquired resistance remains a major clinical problem. To define tumor-intrinsic transcriptional changes associated with acquired resistance, we generated independently derived anti-PD-1-resistant MC-38 colon adenocarcinoma cell lines (MC38-PR) by serial in vivo selection in immunocompetent C57BL/6 mice. Isotype-control-passaged MC38-ISO lines and the parental MC-38 line served as controls. Bulk RNA sequencing was performed to compare parental, isotype-control-passaged, and acquired anti-PD-1-resistant cell lines. These data support a multi-omic investigation of resistance in which independently derived resistant tumors converged on an immunosuppressive, macrophage-skewing tumor program despite retaining antigen-presentation machinery, interferon-gamma responsiveness, and most predicted neoantigens.

  多组学
• Smad4/SKI/SKIL-mediated repression of TGF-β signature is essential for a robust CD8 T cell response [viral vectors RNA-seq]
  GSE325275Mus musculus24 个样本2026-10-29

  Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that regulates both innate and adaptive immune responses. Earlier studies have shown that TGF-β plays a role in promoting T cell exhaustion during the later stages of chronic viral infection. In this study we examined the role of Smad4, a transcription factor downstream of TGF-β signaling, in regulating CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. Surprisingly, we found that Smad4 acts as an intracellular repressor of TGF-β regulated genes during the early effector phase of the CD8 T cell response. Deletion of Smad4 in CD8 T cells resulted in a striking collapse of the virus-specific CD8 T cell response between day 5 to day 8 after LCMV clone 13 infection, with a 50–100-fold reduction in the number of LCMV-specific CD8 T cells at day 8. Both the stem-like and effector CD8 T cells generated in the absence of Smad4 have a dysregulated transcriptional and epigenetic program with elevated TGF-β signature. We show that Smad4 directly binds to several TGF-β target genes and other key genes involved in T cell survival and differentiation and regulates histone modifications and chromatin accessibility at these loci. Deletion of both TGF-β receptor II and Smad4 in antigen-specific CD8 T cells did not rescue the CD8 T cell response. This demonstrates that TGF-β target genes must be actively repressed by Smad4 intracellularly during the effector phase of the CD8 T cell response even in the absence of extracellular TGF-β signaling. By enforced expression of WT and mutant Smad4 in Smad4-KO CD8 T cells using retrovirus vectors, we show that the interaction between Smad4 and the TGF-β signaling repressors, SKI/SKIL, plays a critical role in antigen-specific CD8 T cells during the effector phase by turning off the TGF-β signature, whereas the interaction between Smad4 with TGF-β-induced phospho-Smad2/3 is dispensable at this stage. Consistent with this essential role of Smad4 during the effector phase, Smad4/SKI/SKIL interaction is also required for a robust CD8 T cell response against tumors and acute viral infection. Our findings documenting the striking requirement for Smad4-SKI-SKIL mediated restraint of TGF-β-associated program during the effector phase of the CD8 T cell response have implications for developing immunotherapeutic approaches against chronic viral infections and cancer.
• Smad4/SKI/SKIL-mediated repression of TGF-β signature is essential for a robust CD8 T cell response [kockout infection RNA-seq]
  GSE325274Mus musculus18 个样本2026-10-29

  Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that regulates both innate and adaptive immune responses. Earlier studies have shown that TGF-β plays a role in promoting T cell exhaustion during the later stages of chronic viral infection. In this study we examined the role of Smad4, a transcription factor downstream of TGF-β signaling, in regulating CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. Surprisingly, we found that Smad4 acts as an intracellular repressor of TGF-β regulated genes during the early effector phase of the CD8 T cell response. Deletion of Smad4 in CD8 T cells resulted in a striking collapse of the virus-specific CD8 T cell response between day 5 to day 8 after LCMV clone 13 infection, with a 50–100-fold reduction in the number of LCMV-specific CD8 T cells at day 8. Both the stem-like and effector CD8 T cells generated in the absence of Smad4 have a dysregulated transcriptional and epigenetic program with elevated TGF-β signature. We show that Smad4 directly binds to several TGF-β target genes and other key genes involved in T cell survival and differentiation and regulates histone modifications and chromatin accessibility at these loci. Deletion of both TGF-β receptor II and Smad4 in antigen-specific CD8 T cells did not rescue the CD8 T cell response. This demonstrates that TGF-β target genes must be actively repressed by Smad4 intracellularly during the effector phase of the CD8 T cell response even in the absence of extracellular TGF-β signaling. By enforced expression of WT and mutant Smad4 in Smad4-KO CD8 T cells using retrovirus vectors, we show that the interaction between Smad4 and the TGF-β signaling repressors, SKI/SKIL, plays a critical role in antigen-specific CD8 T cells during the effector phase by turning off the TGF-β signature, whereas the interaction between Smad4 with TGF-β-induced phospho-Smad2/3 is dispensable at this stage. Consistent with this essential role of Smad4 during the effector phase, Smad4/SKI/SKIL interaction is also required for a robust CD8 T cell response against tumors and acute viral infection. Our findings documenting the striking requirement for Smad4-SKI-SKIL mediated restraint of TGF-β-associated program during the effector phase of the CD8 T cell response have implications for developing immunotherapeutic approaches against chronic viral infections and cancer.
• Two-phase NEUROD1 pioneer activity regulates temporal differentiation and subtype specification of auditory neurons [CUTTag_E115]
  GSE315627Mus musculus12 个样本2026-10-29

  The transcriptional and epigenetic mechanisms that govern neuronal subtype differentiation and diversification remain poorly defined, with auditory neurons among the least understood. Here, we investigate the role of the proneural factor NEUROD1 using a delayed, self terminating conditional knockout (Neurod1ST) mouse model that bypasses the early neuronal loss observed in germline mutants. By integrating NEUROD1 chromatin binding and histone profiling at E11.5 with transcriptomic analyses at E11.5, E14.5, and E18.5, we show that NEUROD1 is essential for coordinating the timing of neuronal differentiation. Neurod1 deletion prolongs progenitor-like states while prematurely accelerating differentiation and axonogenesis programs, reflecting the collapse of NEUROD1-dependent transcriptional networks and recruitment of compensatory pathways. NEUROD1 preferentially binds enhancers of neuronal differentiation genes and promotes their transition to active chromatin states, consistent with a pioneer factor function. Loss of Neurod1 disrupts these epigenomic transitions, alters neuronal migration and innervation trajectories, and ultimately leads to neuronal instability and apoptosis. During spiral ganglion neuron diversification, Neurod1ST neurons prematurely activate maturation markers and fail to generate Type Ic, instead adopting a Type Ib-like identity. These findings establish NEUROD1 as a central regulator that synchronizes differentiation, stabilizes neuronal identity, and shapes auditory neuron subtype diversity in the developing inner ear
• Two-phase NEUROD1 pioneer activity regulates temporal differentiation and subtype specification of auditory neurons
  GSE315509Mus musculus12 个样本2026-10-29

  The transcriptional and epigenetic mechanisms that govern neuronal subtype differentiation and diversification remain poorly defined, with auditory neurons among the least understood. Here, we investigate the role of the proneural factor NEUROD1 using a delayed, self terminating conditional knockout (Neurod1ST) mouse model that bypasses the early neuronal loss observed in germline mutants. By integrating NEUROD1 chromatin binding and histone profiling at E11.5 with transcriptomic analyses at E11.5, E14.5, and E18.5, we show that NEUROD1 is essential for coordinating the timing of neuronal differentiation. Neurod1 deletion prolongs progenitor-like states while prematurely accelerating differentiation and axonogenesis programs, reflecting the collapse of NEUROD1-dependent transcriptional networks and recruitment of compensatory pathways. NEUROD1 preferentially binds enhancers of neuronal differentiation genes and promotes their transition to active chromatin states, consistent with a pioneer factor function. Loss of Neurod1 disrupts these epigenomic transitions, alters neuronal migration and innervation trajectories, and ultimately leads to neuronal instability and apoptosis. During spiral ganglion neuron diversification, Neurod1ST neurons prematurely activate maturation markers and fail to generate Type Ic, instead adopting a Type Ib-like identity. These findings establish NEUROD1 as a central regulator that synchronizes differentiation, stabilizes neuronal identity, and shapes auditory neuron subtype diversity in the developing inner ear
• Intestinal SAA1 and SAA2 regulate the balance between host inflammatory responses and metabolism
  GSE286869Mus musculus40 个样本2026-10-29

  Since their discovery as acute phase reactants, the SAA proteins have been an important focus of innate immunity research. Most SAA production is in the liver, and despite recent findings of their roles in promoting intestinal immunity, the precise functions of intestinal SAAs have not been well-studied. Validating and using an SAA1/2 double knock-out mouse, we found protective effects of SAA1 and SAA2 mitigating systemic and local inflammatory challenges, along with gene-, sex-, and location-specific responses to gut microbiota perturbations. SAA1 and SAA2 expression supports immunological protection in homeostasis but prioritizes metabolic activities under stress. From this work, we propose a new model in which SAA functions to regulate and integrate the interface between metabolism and host responses to inflammatory insults.

  扰动筛选
• Lobe-specific liver transcriptional responses to portal vein ligation in wild-type and TNFR-knockout mice
  GSE352371Mus musculus22 个样本2026-10-28

  One-color mouse microarray expression profiles from untreated wild-type liver, ligated left and non-ligated right liver lobes after portal vein ligation, and an immediate postoperative sham reference. TNFR-knockout samples provide exploratory genotype comparisons.
• Sodium butyrate alleviates metabolic dysfunction-associated steatotic liver disease by activating PPAR-γ/FUNDC1‑mediated mitophagy to inhibit ferroptosis
  GSE351765Mus musculus18 个样本2026-10-28

  This study aims to elucidate the protective effects and underlying molecular mechanisms of sodium butyrate (NaB), a gut microbiota-derived metabolite, against metabolic dysfunction-associated steatotic liver disease (MASLD). Using high-fat diet (HFD)-fed mice and palmitic acid (PA)-treated hepatocytes, the study seeks to determine whether NaB alleviates hepatic steatosis and injury by restoring iron and redox homeostasis, upregulating glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1), and suppressing ferroptosis. It further aims to investigate whether these protective effects depend on FUN14 domain-containing protein 1 (FUNDC1)-mediated mitophagy, and to identify peroxisome proliferator-activated receptor gamma (PPAR-γ) as an upstream regulator of FUNDC1 expression and mitophagy. Collectively, this study aims to define a PPAR-γ/FUNDC1-mitophagy-ferroptosis axis through which NaB protects against MASLD, thereby linking a gut microbial metabolite to hepatic mitochondrial quality control and providing a potential therapeutic target and nutritional intervention strategy for MASLD.
• Bulk RNA-seq profiling of regulatory and effector T cells of C57BL/6 mice
  GSE350087Mus musculus12 个样本2026-10-28

  Regulatory T cells (Tregs) maintain immune tolerance, whereas effector T cells (Teffs) mediate immune responses. Imbalance between Tregs and Teffs may contribute to immune dysregulation in type 1 diabetes mellitus (T1DM). Here, we performed bulk RNA sequencing of splenic Tregs and Teffs from control and streptozotocin-induced diabetic C57BL/6 mice to characterize disease-associated transcriptional alterations. Tregs in T1DM exhibited enhanced proliferative, effector-associated, and metabolic transcriptional programs, alongside reduced expression of genes involved in immunoregulation, lineage maintenance, tissue homing, metabolic fitness, and stress adaptation. Meanwhile, Teffs adopted a hyperactivated, but functionally imbalanced transcriptional state characterized by enhanced proliferative and inflammatory programs alongside dysregulated metabolic, signaling, and migratory functions. This study identified transcriptional alterations of splenic Tregs and Teffs in control and STZ-induced diabetic C57BL/6 mice, providing candidate molecular markers for further investigation of T-cell dysregulation in T1DM.
• Furan fatty acids reprogram hepatic lipid metabolism via acyl-CoA conjugates in obesity.
  GSE347256Mus musculus24 个样本2026-10-28

  Dietary fish oil (FO) and omega-3 fatty acids are associated with cardiometabolic benefits, yet their molecular mediators remain incompletely defined. Furan fatty acids (FuFAs), a distinct lipid class enriched in FO, have emerged as potential regulators of metabolic health. Here, we identify and quantify FuFA species in prescription omega-3 formulations and natural fish oils, and synthesize structurally engineered analogs designed to isolate antioxidant activity and β-oxidation susceptibility from FuFA bioactivity. In a diet-induced obesity mouse model, both natural and synthetic FuFAs reduced fat accumulation and inflammatory markers, while 11U3-2M additionally produce significant improvement in glucose tolerance, dyslipidemia, and hepatic steatosis. The superior activity of 11U3-2M reflects the stable accumulation of its acyl-CoA conjugate that activates peroxisome proliferator-activated receptor alpha (PPARα) signaling and allosterically inhibits acetyl-CoA carboxylases (ACCs) to reprogram hepatic lipid metabolism. These findings position FuFAs as functional dietary lipids contributing to fish oil’s metabolic effects and define fatty acid structural determinants that govern hepatic metabolic activity.
• Time-resolved RNA-seq reveals a phased transcriptional response to TGFβ stimulation
  GSE343789Mus musculus40 个样本2026-10-28

  Fibroblast differentiation into matrix-producing, contractile myofibroblasts is accompanied by metabolic reprogramming, but whether these changes precede differentiation or arise from the activated phenotype remains unclear. To define when transcriptional remodeling emerges after TGFβ stimulation, we performed bulk RNA-seq on cardiac fibroblasts treated with TGFβ or bFGF for 1, 6, 12, 24, or 48 h. Our transcripomics revealed only 394 genes were differentially expressed at 1 h, but 4,188 DEGs were detected by 6 h, with the total DEG burden peaking at 24 h. These findings support a phased, time-dependent remodeling of the cardiac fibroblast transcriptome in response to TGFβ relative to bFGF in which an initially limited response occurs at 1 h, expands substantially by 6 h, and subsequently encompasses cell cycle regulation, stress responses, developmental- and differentiation-associated programs, cell adhesion, and extracellular matrix remodeling.
• Real-world river water organic pollutant mixture induces ovarian hyperandrogenism via aryl hydrocarbon receptor activation [follicular]
  GSE343593Mus musculus10 个样本2026-10-28

  Humans are exposed to complex mixtures of endocrine-disrupting chemicals (EDCs) in the real world. Most prior studies, however, focus on individual EDCs. Here, we investigated the ovarian impact of organic pollutant mixtures extracted from the Raritan River, a heavily industrialized watershed in central New Jersey, using a three-dimensional (3D) in vitro ovarian follicle culture system. Ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) identified organic pollutant mixtures dominated by alkylphenols, pharmaceuticals, per- and polyfluoroalkyl substances (PFAS), and phthalates, together with previous reports demonstrating that the Raritan River also contains hydrophobic persistent organic pollutants (POPs), including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and dioxins. In vitro exposure to the Raritan River-derived EDC mixture did not affect follicle growth and ovulation but dose-dependently increased preovulatory testosterone secretion while suppressing postovulatory progesterone production. Transcriptomic analysis, Gene set enrichment analysis (GSEA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and in situ RNA hybridization revealed widespread reprogramming of follicular somatic cell gene expression, including altered steroidogenic pathways and activation of aryl hydrocarbon receptor (AhR) signaling. An established AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), reproduced the phenotype of EDC mixture-induced hyperandrogenism, which was reversed by a selective AhR inhibitor. Together, this study demonstrates that real-world EDC mixtures, particularly AhR-activating chemicals, disrupt ovarian steroidogenesis and induce hyperandrogenism, highlighting EDC mixtures as an underrecognized mechanism linking aquatic pollution to impaired women’s reproductive health.
• mRNA and miRNA Sequencing Identifies Increased Oxidative Stress Pathways in a Mouse Model of Ethanol Exacerbation of Colitis [mRNA Seq]
  GSE329642Mus musculus24 个样本2026-10-28

  Alcohol consumption has been found to worsen the pathology of colitis. To elucidate the underlying mechanism, we performed both miRNA and mRNA sequencing of the large intestinal epithelial cells derived from a murine model of alcohol and colitis. Male C57BL/6 received Dextran Sulfate Sodium (DSS) for 5 days to induce colitis and gavaged with alcohol (~3g/kg) or water for 3 days. Three hours after the final gavage, the mice were euthanized and colon lengths were measured, followed by epithelial cell isolation. RNA, including miRNA, was isolated from the colonic epithelial cells and sent to Novogene for mRNA and miRNA sequencing. Analysis comparing DSS Ethanol vs Sham Vehicle mice showed 3931 significantly upregulated genes and 3788 significantly downregulated genes. Functional enrichment analysis of GO and KEGG pathways showed enrichment of superoxide anion generation and HIF-1 signaling pathways, both related to oxidative stress. DSS Ethanol compared to DSS Vehicle resulted in 921 significantly upregulated and 1072 significantly downregulated genes (Padj<0.05) with functional enrichment analysis showing the term with the highest fold enrichment was superoxide anion generation. We further confirmed the RNA and protein expression of NOS2, CYBB, and NCF1 which are involved in nitric oxide and superoxide production. miRNA sequencing revealed 84 differentially expressed miRNAs comparing DSS Ethanol to DSS Vehicle. Functional enrichment analysis of predicted targets of these miRNAs also showed enrichment in superoxide anion generation. These results suggest that combined ethanol and DSS exposure may increase the production of reactive oxygen species, which further damages the intestinal lining and potentially contributes to the ethanol exacerbation of colitis