Biology subjects

Hirayama, A.

Publications and source records attributed to Hirayama, A..

12 recordsLinked to original sources

bioRxiv2026

Inflammatory signaling drives SQSTM1-dependent suppression of interferon-γ-induced MHC class I

An immune-inflamed tumor microenvironment features interferon-{gamma} (IFN-{gamma}) and inflammatory cytokines, yet how cancer cells integrate these opposing signals to regulate immunogenicity remains poorly understood. Here, we investigated the effect of interleukin-1{beta} (IL-1{beta}) on IFN-{gamma}-induced major histocompatibility complex class I (MHC-I) expression in non-small cell lung cancer (NSCLC) cells. IL-1{beta} suppressed IFN-{gamma}-induced surface MHC-I expression despite preserved or enhanced expression of antigen presentation-related genes, indicating post-transcriptional regulation. This effect emerged 12-24 h after stimulation and accompanied accelerated MHC-I turnover without altering total protein abundance. RNA sequencing identified selective induction of autophagy-related genes under combined IFN-{gamma} and IL-1{beta} stimulation. Immunofluorescence and biochemical analyses demonstrated MHC-I redistribution to autophagosome-lysosome compartments. Mechanistically, the selective autophagy receptor SQSTM1 associated with MHC-I and was required for its surface downregulation, whereas NBR1 depletion and autophagy or lysosomal inhibition failed to restore MHC-I expression, indicating a nonredundant role for SQSTM1. These findings identify post-translational MHC-I trafficking as an underappreciated regulatory layer linking inflammatory signaling to the canonical IFN-{gamma}-MHC-I axis and reveal an SQSTM1-dependent mechanism controlling MHC-I surface availability in immune-inflamed tumors.

immunology↗

bioRxiv2026

MassBank Human: The annotated human metabolome

Mass spectrometry-based metabolomics is essential for deciphering human metabolic functions and metabolite dark matter. However, the dark matter of the human metabolome is intricately hidden. Therefore, we developed MassBank Human, a curated library that distills 36,512,540 MS2 spectra from 76 public human datasets into 203,886 high-quality spectra via spectral averaging, recalibration, and filtering to achieve high mass accuracy. We further used three metabolite annotation tools and developed a Zipf-Bayesian rank aggregation framework to aggregate their rankings with false discovery rate control. This framework assigned molecular formulas, chemical classes, and planar structures to 55,564, 22,619, and 14,198 spectra, respectively. Approximately half of the annotated structures potentially originated from food, pollutants, or gut microbiota. In a metabolome analysis of colorectal cancer cells, MassBank Human doubled structural annotation coverage (10.6% to 21.2%), identifying acetylated polyamines as markers of metabolic rewiring. This community resource provides an annotated foundation for exploring human metabolomes.

bioinformatics↗

bioRxiv2026

Coordinated expansion of CD163⁺ monocytes and immature CD177⁺ neutrophils marks severe neurotoxicity after CD19 CAR T cell therapy

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a major complication after CAR T cell therapy, but its underlying mechanisms remain poorly understood. We performed longitudinal immune profiling of paired whole blood and serum samples from patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) treated with CD19 CAR T cells. At peak neurotoxicity, high-dimensional mass cytometry and serum proteomics identified the expansion of CD163 monocytes and immature CD10lowCD101low neutrophils correlated with elevated serum ST2 and IL-2RA concentrations. Integrative immune module analysis identified these features among the strongest predictors of ICANS severity. Independent single-cell transcriptomic profiling validated the emergence of immunoregulatory CD163 monocytes and identified CD177 as a biomarker of ICANS-associated immature neutrophils. Together, these findings reveal a coordinated myeloid inflammatory network associated with ICANS and nominate candidate biomarkers and therapeutic targets for improving the safety of CAR T cell therapy. SignificanceWe demonstrate that immunoregulatory CD163+ monocytes and immature, activated CD177hiCD10lowCD101low neutrophils emerge in patients with moderate to severe ICANS at peak toxicity following CD19 CAR T cell therapy. These findings identify an uncharacterized myeloid network potentially contributing towards ICANS pathogenesis.

immunology↗

bioRxiv2026

Folate-dependent one-carbon metabolism controls meiotic and post-meiotic epigenome remodeling in the male germline

Environmental exposures can influence offspring health through epigenetic alterations in the male germline. Folate deficiency, a dietary perturbation that disrupts one-carbon metabolism and S-adenosylmethionine (SAM) production, has been linked to altered histone methylation and developmental abnormalities in offspring. However, when and how folate availability shapes the germline epigenome during spermatogenesis remains unclear. In this study, unbiased metabolomic profiling of spermatogenic cells uncovers stage-specific metabolic remodeling, including downregulation of serine- glycine-one-carbon (SGOC) metabolism in meiotic spermatocytes. Using a post-weaning folate-deficient mouse model, we investigate how folate availability influences germline epigenome establishment during spermatogenesis. Consistent with this metabolic transition, genome-wide chromatin accessibility profiling demonstrates extensive, stage-dependent remodeling under folate-deficient conditions, particularly in meiotic spermatocytes and post-meiotic spermatids. These accessibility changes display cell-type-specific genomic distributions and preferential localization to repressive chromatin compartments in post-meiotic cells. Histone modification analyses further reveal bidirectional redistribution of the active histone mark H3K4me3 in round spermatids. Although genome-wide distribution of the repressive mark H3K27me3 remains largely stable, folate deficiency alters its nuclear organization. Notably, a subset of H3K4me3 alterations established in post-meiotic cells is retained in mature sperm, providing a mechanistic link between paternal metabolic perturbation and the germline epigenome. Together, these findings demonstrate that folate availability shapes germline epigenome establishment through stage-specific metabolic and chromatin remodeling during spermatogenesis, revealing a metabolic basis for paternal environmental effects on the germline epigenome.

developmental biology↗

bioRxiv2025

The Gibbs free energy landscape based on liver metabolome revealed thermodynamic robustness against fasting and obesity

Mammalian liver metabolism undergoes a substantial shift during fasting. Thermodynamic principles impose fundamental constraints on metabolism, and the Gibbs free energy change of reaction ({Delta}rG') indicates the reactions direction and distance from equilibrium. However, {Delta}rG' landscapes in intact mammalian organs remain largely uncharacterized. Here, we mapped {Delta}rG' profile of glucose metabolism in mouse liver during fasting, using experimentally measured absolute metabolite concentrations and a newly developed computational method, GLEAM. We found that despite large metabolite fluctuations during fasting, the corresponding {Delta}rG's remained robust, even for reactions reversing the direction between glycolysis and gluconeogenesis. A remarkable thermodynamic robustness is found in maintaining potential candidates of rate-limiting steps during fasting. This robustness is achieved by expending substantial costs for enzyme expressions, contributing to efficient switching from glycolysis to gluconeogenesis. Furthermore, obese mouse liver also showed thermodynamic robustness despite obesity-induced metabolic disruption. Our framework provided a novel thermodynamic perspective on intact organ metabolism, demonstrating that the liver robustly maintains thermodynamic characteristics favorable for metabolic control by buffering metabolite concentration differences.

systems biology↗

bioRxiv2025

Global loss of responsiveness in key regulator metabolites and elevated enzyme proteins as metabolic dysregulation in skeletal muscle and liver of obese mice during starvation

Starvation induces complex metabolic adaptations in skeletal muscle, a key tissue for maintaining energy homeostasis; however, these adaptations are largely impaired in obesity. How obesity alters global metabolic adaptations to starvation in skeletal muscle remains unclear. Here, we analyzed the metabolic adaptations on a trans-omics scale during starvation in skeletal muscle from wild-type (WT) and leptin-deficient obese (ob/ob) mice. We measured multi-omics data during starvation and constructed global trans-omics networks in WT and ob/ob mice. We found that starvation induces "responsiveness" in WT mice, characterized by increases or decreases in key regulator metabolites, including ATP and AMP, as well as enzyme proteins, leading to global regulation of metabolic pathways, which was lost in ob/ob mice. In contrast, during starvation, ob/ob mice exhibit "difference" in comparison to WT mice, manifested by the persistently elevated expression of metabolic enzymes. These features were similarly found in liver, another key metabolic organ. Thus, global loss of responsiveness and elevated enzyme proteins are systemic features of metabolic dysregulation in ob/ob mice.

systems biology↗

bioRxiv2024

Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in liver of healthy and obese mice

Adaptation to starvation is a multi-molecular and temporally ordered process, that could be impaired in obesity. To elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process, we measured time course multiomic data in the liver of wild-type (WT) and leptin-deficient obese (ob/ob) mice during starvation. Using the measured data, we constructed a starvation-responsive metabolic network, that is a transomic network including responsive molecules and their regulatory relationships during starvation, and analyzed the structure of the network. In WT mice, ATP and AMP, the energy indicators, regulated various metabolic reactions in the network as the hub molecules, both of which were not responsive in ob/ob mice. However, the structural properties of the network were maintained in ob/ob mice. In WT mice, the molecules in the network were temporally ordered through metabolic process coordinated by the hub molecules including ATP and AMP and were positively or negatively co-regulated. By contrast, both temporal order and co-regulation were disrupted in ob/ob mice. Taken together, the starvation-responsive metabolic network is structurally robust, but temporally vulnerable by the loss of responsiveness of the hub molecules in obesity. In addition, we proposed a potential therapeutic target to treat the negative effects of obesity on intermittent fasting to extend lifespan. One Sentence SummaryHub molecules activate or inhibit various molecules in a temporally ordered manner in healthy liver, and the regulatory network is structurally robust but temporally vulnerable to obesity.

systems biology↗

bioRxiv2024

Transcriptome analysis of the tardigrade Hypsibius exemplaris exposed to the DNA-damaging agent bleomycin

Tardigrades are microscopic animals that are renowned for their capabilities of tolerating near-complete desiccation by entering an ametabolic state called anhydrobiosis. However, many species also show high tolerance against radiation in the active state as well, suggesting cross-tolerance via the anhydrobiosis mechanism. Previous studies utilized indirect DNA damaging agents to identify core components of the cross-tolerance machinery; however, it was difficult to distinguish whether transcriptomic changes were the result of DNA damage or residual oxidative stress. To this end, we performed transcriptome analysis on bleomycin-exposed Hypsibius exemplaris. We observed induction of several tardigrade-specific gene families that may be the core components of the cross-tolerance mechanism. We also identified an enrichment of the tryptophan metabolism pathway, which metabolomic analysis suggested the engagement of this pathway in stress tolerance. These results provide several candidates for the core component of the cross-tolerance, as well as possible anhydrobiosis machinery.

molecular biology↗

bioRxiv2023

Trans-omic analysis reveals opposite metabolic dysregulation between feeding and fasting in liver associated with obesity

Dysregulation of liver metabolism associated with obesity during feeding and fasting leads to the breakdown of metabolic homeostasis. However, the underlying mechanism remains unknown. Here, we measured multi-omics data in the liver of wild-type and leptin-deficient obese (ob/ob) mice at ad libitum feeding, and constructed a differential regulatory trans-omic network of metabolic reactions. We compared the trans-omic network at feeding with that at 16 h-fasting constructed in our previous study. Intermediate metabolites in glycolytic and nucleotide metabolism decreased in ob/ob mice at feeding but increased at fasting. Allosteric regulation reversely shifted between feeding and fasting, generally showing activation at feeding while inhibition at fasting in ob/ob mice. Transcriptional regulation was similar between feeding and fasting, generally showing inhibiting transcription factor regulations, activating enzyme protein regulations in ob/ob mice. The opposite metabolic dysregulation between feeding and fasting characterizes breakdown of metabolic homeostasis associated with obesity.

systems biology↗

bioRxiv2022

In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and genetically obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

systems biology↗

bioRxiv2021

Omics-based label-free metabolic flux inference reveals dysregulation of glucose metabolism in liver associated with obesity

Glucose homeostasis is maintained by modulation of metabolic flux. Enzymes and metabolites regulate the involved metabolic pathways. Dysregulation of glucose homeostasis is a pathological event in obesity. Analyzing metabolic pathways and the mechanisms contributing to obesity-associated dysregulation in vivo is challenging. Here, we introduce OMELET: Omics-Based Metabolic Flux Estimation without Labeling for Extended Trans-omic Analysis. OMELET uses metabolomic, proteomic, and transcriptomic data to identify changes in metabolic flux, and to quantify contributions of metabolites, enzymes, and transcripts to the changes in metabolic flux. By evaluating the livers of fasting ob/ob mice, we found that increased metabolic flux through gluconeogenesis resulted primarily from increased transcripts, whereas that through the pyruvate cycle resulted from both increased transcripts and changes in substrates of metabolic enzymes. With OMELET, we identified mechanisms underlying the obesity-associated dysregulation of metabolic flux in liver. HighlightsO_LIWe created OMELET to infer metabolic flux and its regulation from multi-omic data. C_LIO_LIGluconeogenic and pyruvate cycle fluxes increased in fasting ob/ob mice. C_LIO_LITranscripts increases mediated the increase in gluconeogenic fluxes in ob/ob mice. C_LIO_LIIncreases in transcripts and substrates enhanced pyruvate cycle flux in ob/ob mice. C_LI

systems biology↗

bioRxiv2019

Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in the healthy and obese states, we constructed and analyzed trans-omic glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multi-omic time-course data from wild-type (WT) and leptin-deficient obese (ob/ob) mice after orally administered glucose. In WT mice, metabolic reactions were rapidly regulated (within 10 minutes of oral glucose administration) primarily by glucose-responsive metabolites, especially ATP and NADP+, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-dependent glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, most rapid regulation by glucose-responsive metabolites was absent; instead, glucose administration produced slow changes in the expression of metabolic enzyme-encoding genes to alter metabolic reactions in a time scale of hours. Few common regulatory events occurred in both the healthy and obese mice. Thus, our trans-omic network analysis revealed regulation of liver metabolism in response to glucose is mediated through different mechanisms in the healthy and obese states: Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.\n\nOne Sentence SummaryRapid changes in regulatory metabolites and gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.

systems biology↗