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PubMed2024

Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach.

Biological mechanisms related to cancer development can leave distinct molecular fingerprints in tumours. By leveraging multi-omics and epidemiological information, we can unveil relationships between carcinogenesis processes that would otherwise remain hidden. Our integrative analysis of DNA methylome, transcriptome, and somatic mutation profiles of kidney tumours linked ageing, epithelial-mesenchymal transition (EMT), and xenobiotic metabolism to kidney carcinogenesis. Ageing process was represented by associations with cellular mitotic clocks such as epiTOC2, SBS1, telomere length, and PBRM1 and SETD2 mutations, which ticked faster as tumours progressed. We identified a relationship between BAP1 driver mutations and the epigenetic upregulation of EMT genes (IL20RB and WT1), correlating with increased tumour immune infiltration, advanced stage, and poorer patient survival. We also observed an interaction between epigenetic silencing of the xenobiotic metabolism gene GSTP1 and tobacco use, suggesting a link to genotoxic effects and impaired xenobiotic metabolism. Our pan-cancer analysis showed these relationships in other tumour types. Our study enhances the understanding of kidney carcinogenesis and its relation to risk factors and progression, with implications for other tumour types.

Kidney Neoplasms↗

PubMed2025

Time-course transcriptome and proteomic dynamics during the de novo shoot organogenesis in Chinese fir (Cunninghamia lanceolata).

De novo shoot organogenesis (DNSO) enables plants to regenerate shoots from various explants, offering valuable opportunities for research and plant biotechnology applications. While significant progress has been made in understanding regeneration in angiosperms, the regulatory mechanisms in gymnosperms, particularly Chinese fir (Cunninghamia lanceolata), remain poorly understood, despite its importance as a key timber species in China. This study successfully established an efficient DNSO protocol for Chinese fir, identifying six distinct stages in the process through cellular-level analysis. Time-course transcriptome and proteomics analyses revealed dynamic changes in mRNA and protein levels during regeneration. Notably, proteins showed more significant alterations across a broad range of biological processes, often independent of corresponding mRNA changes. Key pathways associated with ethylene metabolism and abiotic stress responses were enriched, highlighting their critical roles in regeneration. Further experiments confirmed that moderate osmotic stress treatments (150 mm mannitol) and ethylene treatment (100 μm ACC and 5 μm AgNO3) substantially enhanced DNSO efficiency. In summary, this study uncovers the molecular mechanisms underlying Chinese fir DNSO, providing valuable insights into improving plant regeneration efficiency in this economically important species. These findings contribute to advancements in plant biotechnology and sustainable forestry practices.

Cunninghamia↗

PubMed2002

The yeast transcriptome in aerobic and hypoxic conditions: effects of hap1, rox1, rox3 and srb10 deletions.

The transcriptome of Saccharomyces cerevisiae was screened using the high-density membrane hybridization method, under aerobic and hypoxic conditions, in wild-type and mutant backgrounds obtained by the disruption of the genes encoding the regulatory proteins Hap1, Rox1 and the Srb10 and Rox3 subunits of RNA polymerase II holoenzyme. None of the mutations studied was able to fully overcome the wild-type hypoxic response. Deletion of the hap1 gene changed the expression profiles of individual open reading frames (ORFs) under both aerobic and hypoxic conditions. Major changes associated with rox3 deletion were related to the hypoxic activation. Rox3 also caused a repressor effect (oxygen-independent) on a subset of genes related to subtelomeric proteins. With regard to the effect brought about by the deletion of rox1 and srb10, correspondence cluster analysis revealed that the transcriptome profile in aerobic conditions is very similar in the wild-type and both deletion strains. In contrast, however, differences were found during hypoxia between the subgroup formed by wild-type and the Deltarox1 deletant compared with the Deltasrb10 deletant. An analysis of selected ORFs responding to hypoxia, in association with a dependence on the regulatory factors studied, made it possible to identify the clusters that are related to different regulatory circuits.

Aerobiosis↗

PubMed2024

Single cell RNA sequencing provides novel cellular transcriptional profiles and underlying pathogenesis of presbycusis.

Age-related hearing loss (ARHL) or presbycusis is associated with irreversible progressive damage in the inner ear, where the sound is transduced into electrical signal; but the detailed mechanism remains unclear. Here, we sought to determine the potential molecular mechanism involved in the pathogeneses of ARHL with bioinformatics methods. A single-cell transcriptome sequencing study was performed on the cochlear samples from young and aged mice. Detection of identified cell type marker allowed us to screen 18 transcriptional clusters, including myeloid cells, epithelial cells, B cells, endothelial cells, fibroblasts, T cells, inner pillar cells, neurons, inner phalangeal cells, and red blood cells. Cell-cell communications were analyzed between young and aged cochlear tissue samples by using the latest integration algorithms Cellchat. A total of 56 differentially expressed genes were screened between the two groups. Functional enrichment analysis showed these genes were mainly involved in immune, oxidative stress, apoptosis, and metabolic processes. The expression levels of crucial genes in cochlear tissues were further verified by immunohistochemistry. Overall, this study provides new theoretical support for the development of clinical therapeutic drugs.

Animals↗

PubMed2025

MOADE: a multimodal autoencoder for dissociating bulk multi-omics data.

In single cell biology, the complexity of tissues may hinder lineage cell mapping or tumor microenvironment decomposition, requiring digital dissociation of bulk tissues. Many deconvolution methods focus on transcriptomic assay, not easily applicable to other omics due to ambiguous cell markers and reference-to-target difference. Here, we present MOADE, a multimodal autoencoder pipeline linking multi-dimensional features to jointly predict personalized multi-omic profiles and cellular compositions, using pseudo-bulk data constructed by internal non-transcriptomic reference and external scRNA-seq data. MOADE is evaluated through rigorous simulation experiments and real multi-omic data from multiple tissue types, outperforming nine deconvolution pipelines with superior generalizability and fidelity.

Humans↗

PubMed2015

Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock.

INTRODUCTION: We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock. METHODS: We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients. RESULTS: We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients' plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states. CONCLUSIONS: We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population's age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.

Adult↗

PubMed2001

Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

Animals↗

PubMed2026

Investigating overflow metabolism in heterotrophic cultures of the green alga Chromochloris zofingiensis.

Chromochloris zofingiensis is of interest for its ability to perform a reversible trophic switch in the presence of glucose that is characterized by a shutdown of photosynthesis and an accumulation of energy storage metabolites. Previous work has shown that this trophic switch is accompanied by overflow metabolism and the production of lactate in aerobic conditions. This trophic switch is not observed in nutrient replete media. We utilized isotopically assisted metabolic flux analysis to characterize intracellular flux distributions that are associated with different metabolic phenotypes observed in this organism in different media formulations in light and dark conditions. The results of this analysis showed that low iron cultures have no flux through carbon fixation reactions, and that the carbon flux entering the TCA cycle in these cultures is approximately 40 % lower than that in iron replete cultures grown heterotrophically. This analysis was complemented with transcriptomics data collected for C. zofingiensis grown in iron limited conditions to provide further evidence towards the negative impact of iron limitation on both photosynthetic and respiratory activity. Overflow metabolism allows this alga to compensate for the lower energy production that results from iron limitation. This work highlights how nutrient availability can lead to changes in the metabolism of C. zofingiensis.

Iron↗

PubMed2025

OmicsTweezer: A distribution-independent cell deconvolution model for multi-omics Data.

Cell deconvolution estimates cell type proportions from bulk omics data, enabling insights into tissue microenvironments and disease. However, practical applications are often hindered by batch effects between bulk data and referenced single-cell data, a challenge that is frequently overlooked. To address this discrepancy, we developed OmicsTweezer, a distribution-independent cell deconvolution model. By integrating optimal transport with deep learning, OmicsTweezer aligns simulated and real data in a shared latent space, effectively mitigating data shifts and inter-omics distribution differences. OmicsTweezer is versatile, capable of deconvolving bulk RNA-seq, bulk proteomics, and spatial transcriptomics. Extensive evaluations on simulated and real-world datasets demonstrate its robustness and accuracy. Furthermore, applications in prostate and colon cancer showcase OmicsTweezer's ability to identify biologically meaningful cell types. As a unified deconvolution framework for multi-omics data, OmicsTweezer offers an efficient and powerful tool for studying disease microenvironments.

Humans↗

PubMed2026

Multi-omics reveal molecular changes during suspension adaptation of HEK293 cells.

Human embryonic kidney 293 (HEK293) cells have been successfully adapted from adherent to suspension culture and widely applied in both scientific research and the pharmaceutical industry. Although some studies investigated the variances between established adherent and suspension HEK293 cells of different strains, specific alterations in the cells during this consecutive process of suspension adaptation and possible factors driving this process have not been well described. Here, we adapted adherent HEK293 to suspension with desirable cell growth and high productivity for recombinant adenoviral vectors, and cells at several stages throughout the process were characterized. Slower cell growth, lower glucose uptake, increased lactate production, and weaker cell-surface adhesion were observed in suspension cells compared to their adherent counterparts. We further performed transcriptomics, proteomics, and metabolomics analysis to identify key cellular switches. A total of 2476 differentially expressed genes were found, including 1218 upregulated and 1258 downregulated genes in suspension cells. A similar and correlated pattern was observed in the proteomic study, and 702 differentially expressed metabolites were identified by untargeted metabolomics. In light of enrichment analysis, we summarized that HEK293 adherent cells survived and adapted to suspension culture via structural remodeling, metabolic shift and stress resistance. Our results provide a molecular enlightenment for suspension adaptation and potential directions for rational modification of HEK293 cell lines for future use. KEY POINTS: • Suspension adaptation reduced adhesion and reshaped the HEK293 cytoskeleton. • Multi-omics revealed metabolic rewiring and enhanced stress resistance. • An optimized suspension line outperformed an internal HEK293 suspension reference.

Humans↗

PubMed2025

RNA sequencing offers new diagnostic opportunities in neurodevelopmental disorders: A systematic review.

PURPOSE: Transcriptomics by way of RNA sequencing (RNAseq) has emerged as a means to increase the diagnostic yield in genetic conditions. In this systematic review, we focus on the contribution of transcriptomics to improve the diagnostic yield in neurodevelopmental disorders. METHODS: We performed a systematic literature search in PubMed until January 2024, including articles describing diagnostic RNAseq on at least 1 individual with a primary neurodevelopmental phenotype. We extracted data on cohort size, phenotype, sample tissue, previously used diagnostic methods, added diagnostic yield of RNAseq, the use of control samples, and technical aspects of the RNA sequencing methodology. RESULTS: A total of 17 articles were eligible for inclusion in the systematic review. We found an average added diagnostic yield of 15.5% through RNA sequencing for individuals with neurodevelopmental disorders. There is heterogeneity in the tissue type, reported quality measures, and the computational pipeline. CONCLUSION: The significantly increased diagnostic yield demonstrates the value of this novel tool in the diagnostic setting of neurodevelopmental disorders. Our results offer an overview of common methodologies for RNAseq and allow us to formulate recommendations for genetic labs and clinicians when implementing RNAseq as a diagnostic tool. Lastly, we provide recommendations for future publications to increase transparency and reproducibility.

Humans↗

PubMed2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans↗

PubMed2000

Analysing uncharted transcriptomes with SAGE.

Methods of comprehensive gene expression analysis have traditionally been limited to analysing bulk tissue or millions of cells. New modifications of serial analysis of gene expression (SAGE) have now permitted the analysis of gene expression in cell subpopulations or microanatomic structures, providing access to unexplored transcriptomes of normal and disease biology.

Animals↗

PubMed2024

Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons.

Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/- hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/- transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.

Humans↗

PubMed2025

The offonome reveals on and off states of gene expression near the detection limit of RNA-seq.

RNA-seq, widely used for gene expression profiling, provides nucleotide level genome coverage and summary gene expression values. Generally, low-expressed genes are ignored due to their unfavorable signal-to-noise ratio, however, these genes may offer crucial information, such as detecting rare cells in bulk tissues. In this study, we applied an approach that transforms the expression levels of low-expressed genes into a robust dichotomized on/off state by leveraging similarities in transcript coverage shape. Applied to three human cancer cohorts from the Cancer Genome Atlas (TCGA), chosen based on tissue morphology and anatomic site, we identified genes, the "offonome" near the detection limit, consistently or occasionally off across samples. Genes in the offonome spectrum proved useful for supervised and unsupervised applications, including characterizing oncogenic pathways, and identifying rare populations of cells in bulk tissue. Interrogating the offonome is relevant to bulk tumor analyses like TCGA, potentially expediting gene investigation in low-input situations like single cell RNA-seq.

Humans↗

PubMed2024

Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4+ regulatory T cells by regulating IL2RA.

Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3, CTLA4, and PDCD1), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3), and loss of Treg-mediated suppression.

Humans↗

PubMed2026

Long-read sequencing reveals widespread novel splicing and neojunction-derived neoantigens in nasopharyngeal carcinoma.

The widespread transcriptomic diversity driven by alternative splicing (AS) contributes to all hallmarks of cancer and represents a critical source of neoantigens for personalized immunotherapy. However, unlike other major malignancies, the full repertoire of AS in nasopharyngeal carcinoma (NPC) remains underexplored. Here, we employ long-read sequencing (LR-seq) to generate a high-resolution, isoform-level transcriptomic atlas from a cohort of 14 NPC tumor samples and four immortalized nasopharyngeal epithelial cell lines. We identify a substantial number of full-length novel transcripts (22,687; ∼44.38%), which reveal diverse splicing patterns and previously unannotated splicing events. By integrating short-read RNA-seq data to quantify isoform expression, we discover a subset of novel transcripts that are differentially expressed between tumor samples and immortalized nasopharyngeal epithelial cell lines. Furthermore, LR-seq enables precise identification of chimeric readthrough fusion transcripts, such as CLDN15-FIS1 and FOXRED2-TXN2 Finally, we develop a computational framework, tumor-specific splicing neoantigen detection (TS-SNAD), to predict neoantigens originating from novel exon-exon junctions (neojunctions) in tumor-specific novel transcripts. Using this framework, we identify neojunction-derived neoantigens and experimentally validate the immunogenicity of selected HLA-B*40:01-restricted neoantigens. These neojunction-derived peptides constitute a new class of noncanonical neoantigens with significant potential for developing personalized cancer vaccines for NPC.

Humans↗

PubMed2026

Unveiling m7G modification patterns and causal drivers governing intracranial aneurysm rupture risk through multi-omics validation and m7G-MeRIP-seq profiling.

Intracranial aneurysm (IA) rupture causes severe brain hemorrhage with high mortality, yet its molecular drivers remain unclear and better risk prediction is urgently needed. Using transcriptomics, single-cell analysis, and genetic data, we investigated the role of N7-methylguanosine (m7G) RNA modification in IA. We identified distinct m7G modification patterns, validated their methylation features in patient samples, and incorporated these patterns into a machine learning-based rupture prediction model. The presence and characteristics of m7G patterns significantly improved model performance, achieving high predictive accuracy across three independent cohorts (AUC 0.91-0.95). Genetic analyses further identified three causal m7G-related genes (NSUN2, IFIT5, SNUPN), and laboratory experiments confirmed their altered expression and methylation in ruptured aneurysms. Overall, our findings demonstrate that m7G modifications play a key role in IA rupture. The validated prediction model offers strong clinical potential for rupture risk assessment, and the identified genes represent promising therapeutic targets.

Humans↗