Functional & Integrative Genomics最新文献

{"title":"Single-cell immune landscape of patients with different ovarian reserves during COH","authors":"Le Zhang,&nbsp;Hailong Sun,&nbsp;Xiujuan Chen","doi":"10.1007/s10142-026-01992-z","DOIUrl":"10.1007/s10142-026-01992-z","url":null,"abstract":"<div><p>Assisted reproductive technology (ART) is widely used to treat infertility, a global health burden. Controlled ovarian hyperstimulation (COH) is a crucial first step in ART that enables the collection of a large number of mature oocytes. Ovarian reserve (OR), namely, the number and quality of primordial follicles, indicates female reproductive potential and is an important determinant of infertility treatment outcomes. However, changes in the immune response and related regulatory mechanisms at single-cell resolution in patients with varying levels of OR during COH remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cell (PBMC) samples obtained from 4 patients with a normal OR (N group), 4 with a diminished OR (D group), and 4 with a high OR (H group) before (B group) and after COH (A group). Single-cell transcriptome profiling revealed 20 cell clusters and cell distribution patterns. GDT, CD8 Teff and CD4 naïve T cells were enriched predominantly in the NA, HA and DA groups, respectively. We also identified differentially expressed genes (DEGs) with similar patterns between the NA and NB groups and between the HA and HB groups. An analysis of intercellular communication revealed variable changes in cell–cell interactions, and the candidate ligand–receptor pair HLA-B/KIR3DL2 was identified in the HA group compared with the HB group. Moreover, we detected systematic proinflammatory features in NA and HA patients accompanied by upregulated expression of proinflammatory genes, including JUN, JUNB, NFKBIA, MAP3K8 and CCL5. We also identified essential transcription factors (TFs) related to follicle development and maturation. This study provides new information on the specific regulatory role of the immune response in COH that will facilitate the identification of potential targets to improve infertility treatment outcomes in patients with varying levels of OR.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148615105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developmental dynamics of ovine lung in health and cystic fibrosis at single-cell resolution","authors":"Svyatoslav Tkachenko,&nbsp;Shih-Hsing Leir,&nbsp;Arnaud J. Van Wettere,&nbsp;Iuri Viotti Perisse,&nbsp;Yasmin Mustafa,&nbsp;Cheyenne M. Marriott,&nbsp;Tayler Patrick,&nbsp;Ying Liu,&nbsp;Kenneth L. White,&nbsp;Irina A. Polejaeva,&nbsp;Ann Harris","doi":"10.1007/s10142-026-01981-2","DOIUrl":"10.1007/s10142-026-01981-2","url":null,"abstract":"<div><p>The sheep lung has long been used to model aspects of the human lung, both its normal development and pathological changes that occur in ovine models of lung disease. The similarities between the two species provide an opportunity to investigate phases of lung development that are not accessible for investigation in humans, for example later in gestation. Here we use single cell (sc) RNA-seq to investigate the developmental dynamics of the sheep proximal and distal lung from mid gestation (80 days) through late gestation (120 days) and term (147 days). We identify changes in cell identity and abundance between the time points that illustrate many key features of mesenchymal, endothelial, and epithelial differentiation. Lastly we compare the single cell profiles through development of wildtype (WT) sheep with those of animals of the same breed engineered to have a loss-of-function mutation in the cystic fibrosis transmembrane conductance regulator (<i>CFTR</i>) gene. Mutations in <i>CFTR</i> cause cystic fibrosis (CF) and the <i>CFTR</i>^{<i>−/−</i>} sheep exhibit many features of CF in humans. The results identify cellular signatures in the <i>CFTR</i>^{<i>−/−</i>} lung before birth that may facilitate the understanding of clinical features of CF in early postnatal life.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-026-01981-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148615102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure-informed lung transcriptomic analysis links predicted NNK targets to cell type-specific remodeling programs in idiopathic pulmonary fibrosis","authors":"Kairui Meng,&nbsp;Lu Wang,&nbsp;Xueqing Gong,&nbsp;Wenjun Tang,&nbsp;Guobing Jia,&nbsp;Yanmei Wang,&nbsp;Chengshi He","doi":"10.1007/s10142-026-01980-3","DOIUrl":"10.1007/s10142-026-01980-3","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is associated with cigarette smoking, yet the relationship between the tobacco-specific nitrosamine nicotine-derived nitrosamine ketone (NNK) and IPF-associated lung transcriptional remodeling remains incompletely understood. Here, we developed an exposure-informed computational framework integrating multi-database target prediction, lung single-cell and single-nucleus transcriptomic analysis, co-expression network analysis, bulk lung cohort projection, and exploratory structure-based modeling. Putative human protein targets of NNK were predicted from ChEMBL, PharmMapper, and SwissTargetPrediction, yielding 2,505 nonredundant targets. These targets were intersected with IPF-associated intramodular hub genes identified from cell type-specific weighted gene co-expression network analysis, defining a focused 42-gene ExposureA-core gene set. Projected ExposureA-core scores showed the clearest IPF-control differences in endothelial and epithelial pseudo-bulk profiles. Functional annotation of the training-derived epithelial ExposureA-core Top30 signature highlighted MAPK and p38 MAPK signaling, PI3K-AKT signaling, angiogenesis or vasculature regulation, cell–substrate adhesion, and membrane-, adhesion-, and cytoskeleton-related cellular components, suggesting remodeling- and adhesion-related epithelial transcriptional features in IPF. The fixed epithelial ExposureA-core Top30 signature remained detectable in independent bulk lung transcriptomic cohorts without gene re-selection, coefficient fitting, or score optimization, with exploratory ROC analyses showing apparent IPF-control separation in GSE110147 and GSE92592. Exploratory docking and 100-ns molecular dynamics simulations of selected epithelial Top30-encoded candidates showed that modeled ECE1–NNK, MMP7–NNK, and TGM2–NNK complexes reached dynamic equilibrium, with relatively stable RMSD, radius of gyration, solvent-accessible surface area, residue-level fluctuation, and low-energy conformational states, supporting their structural plausibility as candidate modeled complexes. Overall, this study defines a focused exposure-informed IPF-associated transcriptional framework and prioritizes epithelial remodeling-related candidate features for future experimental validation. These findings support hypothesis-generating computational prioritization rather than direct evidence that NNK drives IPF pathogenesis.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-026-01980-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148615104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LGMN regulates endothelial-to-mesenchymal transition via the p38 MAPK pathway to promote pulmonary fibrosis","authors":"Yuntao Zou,&nbsp;Jiangsheng Zhang,&nbsp;Dongni Chen,&nbsp;Yingxin Zhang,&nbsp;Jiayang Fan,&nbsp;Kaican Cai","doi":"10.1007/s10142-026-01996-9","DOIUrl":"10.1007/s10142-026-01996-9","url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease driven by fibroblast activation and extracellular matrix deposition. Endothelial-to-mesenchymal transition (EndMT) critically contributes to vascular injury and fibrotic remodeling in IPF. Legumain (LGMN), a lysosomal cysteine protease involved in excessive extracellular matrix processing and signaling modulation, has been implicated in vascular remodeling and fibrosis. This study aimed to investigate whether LGMN influences pulmonary fibrosis by regulating the EndMT process. Independent transcriptomic analyses revealed LGMN is significantly upregulated in IPF and associated with poor prognosis. Publicly available single-cell RNA sequencing datasets identify endothelial cells as a major source of elevated LGMN in human IPF and murine fibrosis, with LGMN expression positively correlating with disease severity. Our studies demonstrated that LGMN knockdown in endothelial cells inhibited EndMT and enhanced migratory and tube formation capabilities; conversely, LGMN overexpression promoted EndMT and suppressed these functions. Transcriptomic profiling indicated that LGMN knockdown significantly influenced the p38 MAPK signaling pathway. To validate the mechanism, pharmacological inhibition of p38 MAPK reduced EndMT and partially reversed LGMN overexpression-induced EndMT. In conclusion, these results indicate LGMN promotes pulmonary fibrosis by activating the p38 MAPK pathway to regulate EndMT, suggesting its potential as a therapeutic target for pulmonary fibrosis.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-026-01996-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148615072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of the BCO gene family and its effect on body coloration in Lutjanus erythropterus","authors":"Zhuoxin Lai,&nbsp;Lujun Chen,&nbsp;Lei Song,&nbsp;Wenjun Feng,&nbsp;Yusong Guo,&nbsp;Zhongduo Wang","doi":"10.1007/s10142-026-01985-y","DOIUrl":"10.1007/s10142-026-01985-y","url":null,"abstract":"<div><p>The beta-carotene oxygenase (BCO) gene family plays a key role in carotenoid metabolism, which is closely linked to body color formation in teleosts. However, its function in <i>Lutjanus erythropterus</i> remains unclear. Here, we identified four BCO gene family members in the genome and characterized their evolutionary conservation, tissue-specific expression, and potential roles in pigmentation. Tissue expression profiling revealed high expression of all BCO genes in the heart, with <i>Bco1</i>, <i>Bco1l</i>, and <i>Bco2l</i> also highly expressed in the intestine and liver. Developmental stage analysis showed that <i>Bco1</i> maintained relatively high expression around hatching, and all genes peaked at 3 days post‑hatching (dph). In differently colored skin at 45 dph, <i>Bco1</i> showed the highest expression in white skin, whereas <i>Bco2b</i> expression in black skin was approximately twice that in yellow and white skin. Astaxanthin feeding upregulated BCO expression in multiple tissues. Under different background culture conditions, <i>Bco1</i> and <i>Bco2b</i> exhibited similar expression patterns, which followed a trend similar to total carotenoid content. These findings indicate a correlation between BCO gene expression and the body color of <i>L. erythropterus</i>, suggesting that these genes may serve as candidate genes potentially involved in body color formation in this species.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148615078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of ARGOS-mediated regulation of plant organ size: molecular mechanisms, environmental interactions, and agricultural implications","authors":"Zifan Cui,&nbsp;Dongyu Wen,&nbsp;Jiawen Lou,&nbsp;Jun Cao","doi":"10.1007/s10142-026-01994-x","DOIUrl":"10.1007/s10142-026-01994-x","url":null,"abstract":"<div><p>Improving crop productivity relies on a thorough comprehension of genetic modules that coordinate plant organ growth with environmental adaptation. ARGOS (Auxin-Regulated Gene involved in Organ Size), ARGOS-LIKE (ARL), and Organ Size Related (OSR) proteins constitute a family of small membrane associated proteins widely found in plants, which participate in auxin and ethylene responses, as well as the regulation of cell proliferation and expansion. Functional studies in <i>Arabidopsis</i> and various crops reveal that <i>ARGOS</i> homologs regulate the development of leaves, roots, stems and reproductive organs, with experimental support differing considerably among species and research systems. In <i>Arabidopsis</i>, <i>AtARGOS</i> promotes organ growth mainly by prolonging the cell proliferation period and functions upstream of <i>ANT</i> and <i>CYCD3;1</i> in the genetic pathway. In maize, modifications to <i>ZmARGOS</i> family genes have been proven to improve field performance under drought conditions. Conversely, the connections between ARGOS and light, temperature, ABA, GA and BR signaling are mostly inferred from large scale hormone and growth regulatory networks, rather than confirmed direct mechanisms. Here, we review the current advances in ARGOS/ARL/OSR research, distinguish direct experimental evidence from speculative regulatory models, and explore the prospects of applying promoter engineering, <i>cis</i>-regulatory editing and allele mining to characterize and deploy these genes for crop genetic improvement.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USF1-mediated transcription of PARP1 contributes to sevoflurane-induced pyroptosis in perioperative neurocognitive disorders","authors":"Qingpan Zhao,&nbsp;Jie Fang,&nbsp;Bing Liang,&nbsp;Jianpo Zhu,&nbsp;Yali Zhan,&nbsp;Ziyan Fan,&nbsp;Chiyang Li,&nbsp;Rui Lan","doi":"10.1007/s10142-026-01991-0","DOIUrl":"10.1007/s10142-026-01991-0","url":null,"abstract":"<div><p>Perioperative neurocognitive disorders (POCD) are a class of common complications of central nervous system after general anesthesia and surgery. Sevoflurane (SEV) is a widely used inhalation anesthetic in clinical practice, but the mechanism of SEV-induced neuronal damage has not yet been fully elucidated. This study aimed to investigate the mechanism of SEV-induced neuronal pyroptosis involving upstream stimulatory factor 1 (USF1) and poly (ADP-ribose) polymerase 1 (PARP1). Single-cell RNA sequencing screening on GSE267933 dataset was performed. POCD animal model was established using C57BL/6J mice, and open field test and Y maze test were conducted to assess cognitive function. Cell model was constructed using human cortical neuronal cell line (CP-H120) and mouse hippocampal neuron cells (HT22). Western blot was employed for protein detection. Cell viability was examined using cell counting kit-8. Pyroptosis was evaluated by enzyme-linked immunosorbent assay, lactate dehydrogenase release assay, flow cytometry, and immunofluorescence staining. The binding between USF1 and PARP1 promoter was analyzed by chromatin immunoprecipitation assay, DNA pull-down assay and dual-luciferase reporter assay. Single-cell sequencing analysis on GSE267933 dataset identified that PARP1 was highly expressed in hippocampal neurons after SEV exposure (P &lt; 0.05). PARP1 knockdown improved cognitive dysfunction and pyroptosis in SEV-exposed POCD mice (P &lt; 0.05). PARP1 downregulation inhibited SEV-induced pyroptosis in human neuronal cells (P &lt; 0.05). USF1 served as a transcription factor to promote PARP1 expression (P &lt; 0.05). Silencing USF1 suppressed SEV-induced pyroptosis in human neuronal cells by downregulating PARP1 (P &lt; 0.05). These findings indicated that USF1-mediated upregulation of PARP1 promoted SEV-induced neuronal pyroptosis, suggesting that USF1/PARP1 axis may function as a key regulator in SEV-triggered neuronal damage in POCD.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div><div><p>Sevoflurane up-regulates the expression of USF1, which in turn binds to the PARP1 gene promoter to enhance its transcription, leading to NLRP3 inflammasome activation, caspase-1 cleavage, GSDMD activization and subsequent inflammatory cytokine release, ultimately contributing to neuronal pyroptosis in postoperative cognitive dysfunction.</p></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydrolipoamide dehydrogenase promotes hepatocellular carcinoma progression and modulates cuproptosis-dependent cell death","authors":"Mao-feng Zhong,&nbsp;Yu-yu Guo,&nbsp;Yuan Tian,&nbsp;Tian-xiao Zheng,&nbsp;Lu-yuan Zhu,&nbsp;Juan Du,&nbsp;Wan-fu Lin","doi":"10.1007/s10142-026-01997-8","DOIUrl":"10.1007/s10142-026-01997-8","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is a major cause of cancer deaths with few treatment options. Cuproptosis, a copper-dependent cell death pathway, is a promising therapeutic target for HCC. In the present study, cuproptosis-related genes in HCC were identified from GeneCards, with dihydrolipoamide dehydrogenase (DLD) emerging as the top hub gene via STRING and Cytoscape analysis. DLD was markedly overexpressed in HCC tissues compared to normal liver tissues (<i>P</i> = 4.6 × 10⁻⁵) and was associated with advanced TNM stage, fibrosis, and reduced overall survival in both the TCGA (<i>P</i> = 0.039) and ICGC (<i>P</i> = 0.002) cohorts. Multivariate analysis identified DLD as an independent prognostic factor (HR = 2.533). GSEA indicated that elevated DLD expression was linked to enhanced glycolysis/gluconeogenesis, tricarboxylic acid cycle, and pyruvate dehydrogenase complex regulation pathways. In vitro, knockdown of DLD inhibited HCC cell proliferation and increased cell death. Importantly, depletion of DLD heightened susceptibility to cuproptosis, which was further augmented by elesclomol to intensify cell death, decrease FDX1 expression, and deplete ATP levels, but effects that were reversed by tetrathiomolybdate. In conclusion, DLD promotes HCC progression through regulating cuproptosis sensitivity, serving as both a prognostic biomarker and a potential therapeutic target for enhancing cuproptosis-based therapies in HCC.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148614833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hsa_circ_0006969 aggravates keratinocytes from high-glucose injury by sponging miR-375 to promote USP10 and SCD expression","authors":"Wenjun Yang,&nbsp;Lusha Li,&nbsp;Yang Lv,&nbsp;Jingjing Yuan","doi":"10.1007/s10142-026-01993-y","DOIUrl":"10.1007/s10142-026-01993-y","url":null,"abstract":"<div><p>Diabetic foot ulcer (DFU) is a severe and frequent complication of diabetes, posing a major burden on patient well-being. Although circular RNAs (circRNAs) have been implicated in DFU pathogenesis, many disease-relevant circRNAs remain uncharacterized. Herein, we aimed to identify key circRNAs involved in DFU and elucidate their underlying molecular mechanisms. CircRNA expression profiles of DFU and non-DFU skin tissues were retrieved from the Gene Expression Omnibus (GEO) dataset GSE114248, and weighted gene co-expression network analysis (WGCNA) was applied to screen for DFU-associated hub circRNAs, which were then verified and confirmed by combining RT-qPCR in clinical samples. A high-glucose (HG) - treated human epidermal keratinocyte model was used to mimic the diabetic wound environment. The function of hsa_circ_0006969 was assessed by CCK-8, wound healing, and Western blot assays. Further bioinformatics prediction combined with dual-luciferase reporter, RIP-qPCR, and rescue experiments were performed to clarify molecular mechanism of hsa_circ_0006969. We found that hsa_circ_0006969 was significantly upregulated in skin tissues of DFU patients and HG - treated human epidermal keratinocyte model. The in vitro functional experiments proved that knockdown of hsa_circ_0006969 alleviated high glucose‑induced inhibition of keratinocyte proliferation and migration. Mechanistically, hsa_circ_0006969 acted as a molecular sponge for miR-375, thereby upregulating the expression of USP10 and SCD. Rescue experiments further demonstrated that the protective effect of hsa_circ_0006969 silencing against high‑glucose damage was reversed by miR-375 inhibition, confirming the involvement of the miR-375/USP10/SCD axis. Collectively, our study reveals that hsa_circ_0006969 promotes DFU progression through the miR-375/USP10/SCD axis and may represent a novel therapeutic target for DFU treatment.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single-cell cell-of-origin audit of the lncRNA RMST: bulk expression under-represents its broad neural expression and over-attributes a liver biomarker","authors":"Hidenori Tani","doi":"10.1007/s10142-026-01995-w","DOIUrl":"10.1007/s10142-026-01995-w","url":null,"abstract":"<div><p>Long non-coding RNAs (lncRNAs) are widely nominated as biomarkers from bulk-tissue data, which cannot reveal which cell type carries a transcript or whether a disease change is cell-intrinsic or compositional. Using the lncRNA <i>RMST</i>, I show that bulk expression can misrepresent where a lncRNA resides in <i>both</i> directions, and that cell-of-origin attribution should precede biomarker claims. I combined GTEx with &gt; 40 million single cells and nuclei from the CZ CELLxGENE Census. (i) <i>Under-representation</i>: at single-cell resolution <i>RMST</i> is most broadly detected in brain (17.2% of ~ 29 million cells; 35% of neurons, up to 74% of dopaminergic neurons), confirming its neural role, yet bulk brain expression is low (0.7 TPM) because <i>RMST</i> is broadly but lowly expressed and nuclear-enriched. (ii) <i>Tissue-dependent peripheral carriers</i>: across six non-brain tissues <i>RMST</i>-positive cells are 85.5% stromal/epithelial (hepatocyte 0.02%), and the dominant carrier switches by tissue (cardiac/vascular fibroblasts vs renal/pulmonary/hepatic epithelium); in heart, fibroblasts carry it (79–91% of positive cells), but a disease per-cell change is not robust (bootstrap CI spans zero; within-study flat-to-negative), so I report attribution, not direction. A broad control (<i>KCNQ1OT1</i>: 6.2 vs <i>RMST</i> 0.5 lineages/tissue) confirms <i>RMST</i>’s restriction is gene-specific. (iii) <i>Over-attribution</i>: <i>RMST</i> is undetected in all 411,742 diseased-liver nuclei (<i>NEAT1</i> and <i>MALAT1</i>: ~ 90% of the same nuclei) and near-absent across liver cells, so a reported liver biomarker — including my own prior report — is unattributable. Cell-of-origin attribution, which both rescues an under-counted neural transcript and retracts an over-counted liver biomarker, belongs in the standard workflow for lncRNA biomarkers.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}