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PubMed2026

A nucleolar stress gene signature enables quantitative scoring across multi-omics contexts.

The nucleolus is essential for ribosome biogenesis and cellular homeostasis, and its dysfunction can induce nucleolar stress, a process implicated in cancer and other diseases. However, nucleolar stress is commonly inferred from morphological changes or a limited set of functional assays, and quantitative approaches based on gene expression profiles remain lacking. Here, we integrate literature curation with multi-dataset screening to define a nucleolar stress gene signature and develop a nucleolar stress score (NuS) applicable to bulk transcriptomics, single-cell transcriptomics, proteomics, and spatial transcriptomics. Using this framework, we show in colorectal cancer models that oxaliplatin induces nucleolar stress, suppresses nascent rRNA synthesis, and activates p53 signaling, whereas these responses are attenuated in oxaliplatin-resistant cells. Combined with a ribosome biogenesis activity score (RiboSis), NuS captures related but distinct dimensions of nucleolar function and stratifies tumors into functional states associated with clinical outcomes. NuS-based analysis of perturbational transcriptomes further prioritizes compounds with putative nucleolar stress-inducing activity. Collectively, this study provides a quantitative framework for evaluating nucleolar stress and illustrates its applications in disease stratification and drug mechanism discovery.

Cell Nucleolus↗

PubMed2025

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Journal Article↗

PubMed2006

Integration--a key to success in the genetic dissection of complex diseases?

Complex diseases are polygenic and multifactorial. The outcome of two decades of search for the culprit genes in complex diseases involving the cardiovascular system has been less than satisfactory. Genomic studies using linkage analysis have led so far to the detection of a large number of quantitative trait loci that embed a large number of candidate genes. Transcriptomic studies using differential gene expression profiling and DNA microarrays have also generated hundreds of potential candidate genes. None of these genetic strategies has enabled researchers to reduce the number of genes to a manageable number or to identify the specific culprit genes. We recently proposed that the search for genes involved in complex diseases such as hypertension might benefit from an integration of genomics and transcriptomics as a logical alternative strategy to using either approach alone. We applied this integrated genomic-transcriptomic approach to identify the genes that are involved in the pathogenesis of hypertension in the Sabra rat model of salt susceptibility. We successfully identified seven novel candidate genes for hypertension, an outcome that could not have been achieved by genomics or transcriptomics alone.

Animals↗

PubMed2026

GenOT: generative optimal transport enables spatiotemporal interpolation and generation in cross-platform spatial transcriptomics.

Spatial transcriptomics technologies have revolutionized the analysis of spatial gene expression, yet integrating spatial information and generating data across heterogeneous samples remain challenging. We present GenOT, a generative framework combining multi-scale graph self-supervised contrastive learning with optimal transport barycenter theory for efficient cross-slice and cross-platform spatiotemporal interpolation. The core innovation of GenOT lies in introducing an optimal transport barycenter-based interpolation algorithm, which mathematically models spatial distribution differences across heterogeneous samples to reconstruct spatiotemporal gene expression dynamics. Extensive evaluations demonstrate that GenOT consistently outperforms existing approaches in spatial domain identification, cross-platform interpolation, and developmental trajectory reconstruction.

Spatial Transcriptomics↗

PubMed2026

Representation learning for multi-modal spatially resolved transcriptomics data.

MOTIVATION: Spatial transcriptomics enables in-depth molecular characterization of samples on a morphology and RNA level while preserving spatial location. Integrating the resulting multi-modal data is an unsolved problem, and developing new solutions in precision medicine depends on improved methodologies. RESULTS: We introduce AESTETIK, a convolutional deep learning model that jointly integrates spatial, transcriptomics, and morphology information to learn accurate spot representations. AESTETIK yielded substantially improved cluster assignments on widely adopted technology platforms (e.g. 10x Genomics™, NanoString™) across multiple datasets. We achieved performance enhancement on structured tissues (e.g. brain) with a 21% increase in median ARI over previous state-of-the-art methods. Notably, AESTETIK also demonstrated superior performance on cancer tissues with heterogeneous cell populations, showing a 2-fold increase in breast cancer, 79% in melanoma, and 21% in liver cancer. We expect that these advances will enable a multi-modal understanding of key biological processes. AVAILABILITY AND IMPLEMENTATION: AESTETIK is implemented in Python 3 and is available as open source software at http://www.github.com/ratschlab/aestetik. The Snakemake pipeline for reproducing the results is available at http://www.github.com/ratschlab/st-rep.

Spatial Transcriptomics↗

PubMed2002

Generation of kidney transcriptomes using serial analysis of gene expression.

Chronic renal disease initiation and progression remain incompletely understood. Genomewide expression monitoring should clarify the mechanisms which cause progressive renal disease by determining how clusters of genes coordinately change their activity. Serial analysis of gene expression (SAGE) is a technique of expression profiling which permits simultaneous and quantitative analysis of 9- to 13-bp sequence tags that correspond to unique mRNAs. Key principles of the technique are use of PCR in a manner to minimize distortion and serial concatenation of tags which facilitates sequencing and permits identification of many expressed genes in a single cDNA molecule. Tags are extracted from many concatenated sequences, counted using software, and identified by comparison with existing gene databases. In aggregate, gene expression profiles generated from a tag library comprise a transcriptome which represents a comprehensive and quantitative profile of genes expressed at the time of analysis. These global snapshots of gene expression patterns can better define basic cell biology and provide insights into disease pathogenesis by simultaneously determining the net consequences of gene-gene and gene-environment interactions on expression of thousands of genes. Rather than applying a priori assumptions (i.e., hypothesis testing), transcriptome analysis is hypothesis generating and requires no prior knowledge of gene expression. SAGE kidney transcriptomes, from normal animals and animals with progressive kidney disease, are being produced and can be analyzed for novel pathogenetic mechanisms. The use of SAGE and other genomic and proteomic tools should result in a better understanding of kidney disease pathogenesis and in identification of new therapeutic targets.

Animals↗

PubMed2026

Dual-transcriptomic analysis of human nasal transcriptome and microbiome reveals host-bacteria associations in symptomatic respiratory infection.

BACKGROUND: The human nasopharynx is colonized by a diverse community of commensal microbiota linked to many respiratory diseases, yet their associations with the host remain unclear. RESULTS: In this study, we introduced a dual-transcriptomics analysis strategy, which can characterize the host transcriptome and microbiome from nasal samples simultaneously. We applied this workflow to a local SARS-CoV-2 cohort with 76 asymptomatic infected patients, among whom 52 (68.42%) developed symptomatic infection during a 1-week follow-up period. Nasal swabs were collected from all 76 patients at enrollment and from 73 patients at one-week later follow-up. We detected a median of 8.94% reads that did not map to the human genome across all 149 samples, among which around half (median 49.68%) were successfully mapped to microbiome genome. Meta-transcriptomic analysis detected significantly higher SARS-related coronavirus loads in samples from the symptomatic group at enrollment (P = 0.004), and both groups showed decreased loads one week later (symptomatic, P = 0.001; asymptomatic, P = 0.035). Compared with benchmarking 16 S rRNA sequencing on 53 samples, our computational strategy showed high correlation of relative abundance in all top 20 genera (median Rho = 0.90, Pmax < 0.001). A total of 670 bacteria species were identified to show a relative abundance ≥ 0.01% in at least 10% samples. Differential abundance analysis identified 76 species (DASs) from six phyla with significantly decreased abundance in samples from the symptomatic group (log2(fold change or FC) < -1 and adjusted P < 0.05) compared to the asymptomatic group at enrollment. Integrating these symptom-associated DASs with host's gene expression using an expression quantitative trait bacteria (eQTB) model, we found 45 symptom-associated DASs identified at enrollment were significantly associated with one to 14 genes (adjusted P < 0.05). GSEA showed a series of symptom-associated DASs were significantly correlated with pathways related to olfactory function, keratinocyte differentiation, and DNA methylation. CONCLUSIONS: In summary, our dual-transcriptomic analysis strategy effectively characterized host-microbiome associations, offering insights into microbial contributions to respiratory diseases.

Humans↗

PubMed2006

Comparative transcriptome maps: a new approach to the diagnosis of colorectal carcinoma patients using cDNA microarrays.

The progression of colorectal cancer involves accumulation of various genetic and epigenetic events that dramatically change gene expression. The aim of this study was to investigate a possible new approach to the diagnosis of colorectal carcinoma patients, based on their gene expression profiles. Human 19K cDNA microarrays were used to analyze the gene expression profiles of 18 colorectal carcinoma patients. Transcriptome maps (TMs) were analyzed to detect chromosomal regions that could serve as potential diagnostic markers for colon cancer. A comparison of TMs showed chromosome regions with conserved changes of gene expression typical of colorectal cancer in general, and also patient-specific variable regions. We identified 195 genes with significantly altered expression in colon cancer. Functional analysis of the regulated genes distinguished three main categories: biological processes, cellular components, and molecular functions. We found that different patients had chromosome regions characterized by very similar changes of gene expression, probably linked to the most fundamental events in carcinogenesis. On the other hand, variable chromosome regions can be patient-specific. The variable regions may provide further information on the individual pathogenesis and prognosis of the patient. Comparison of TMs is proposed as a tool to facilitate diagnosis and treatment planning for individual patients.

Biomarkers, Tumor↗

PubMed2004

Preparation of planar retinal specimens: verification by histology, mRNA profiling, and proteome analysis.

PURPOSE: Elucidation of the transcriptome and proteome of the normal retina will be difficult since it is comprised of at least 55 different cell types. However the characteristic layered cellular anatomy of the retina makes it amenable to planar sectioning, enabling the generation of enriched retinal cell populations. The aim of this study was to validate a reproducible method for preparing enriched retinal layers from porcine retina. METHODS: The thicknesses of the retinal photoreceptor, inner nuclear and ganglion cell, and fiber layers were determined by routine histology of cross sections of fresh whole retina mounted on polyvinylidene difluoride (PVDF) membrane. Dissected retina (5 mm2) was placed on PVDF membrane and a series of planar cryosections corresponding to the photoreceptor and inner nuclear layer were removed leaving the ganglion cell and fiber layer which was subsequently detached from the membrane. The retinal specimens were stored at -80 degrees C. Representative planar tissue sections were sonicated in ice-chilled 40 mM ammonium bicarbonate pH 7.9 and aliquots removed for RNA extraction. Quantitative RT-PCR was used to analyze the mRNA expression of genes indicative of specific retinal layers. Ammonium bicarbonate protein extracts were centrifuged, lyophilized and prepared for direct liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis using a Waters Q-Tof Ultima. RESULTS: Histological analysis established the parameters for planar cryosectioning: photoreceptor layer (69+/-1.8 microm), outer plexiform (11+/-0.6 microm), inner nuclear layer (28+/-0.5 microm), inner plexiform, ganglion cell and fiber layer (100+/-5.3 microm). Gene expression profiling provided an independent method for validating the respective retinal preparations. For example, glial fibrillary acidic protein (GFAP) was expressed up to 21 fold higher in the inner retinal "ganglion cell enriched" fraction than in the outer retinal "photoreceptor enriched" fraction. The pattern was reversed for blue cone opsin, which was expressed up to 24 fold higher in the "photoreceptor enriched" fraction. Endogenous protein fragments indicative of each layer were identified by mass spectrometry and de novo sequence data obtained. CONCLUSIONS: Combined histological and mRNA expression profiling has confirmed the development of a reproducible method for generating validated porcine retinal layers enriched for specific cell types. Direct proteome analysis detected endogenous peptide fragments of characteristic retinal proteins. Further analysis of these enriched retinal cell preparations will facilitate a more selective investigation of the retinal transcriptome and proteome than studies of the intact retina.

Anatomy, Cross-Sectional↗

PubMed2005

Impact of haloperidol and risperidone on gene expression profile in the rat cortex.

Despite the clinical efficacy of the most thoroughly studied conventional neuroleptic agent haloperidol, and the atypical antipsychotic risperidone is well established, little information is available on their molecular effects. Recent advances in high-density DNA microarray techniques allow the possibility to analyze thousands of genes simultaneously for their differential gene expression patterns in various biological processes, and to determine mechanisms of drug action. The aim of this series of experiments was to gain experience in antipsychotic gene-expression profiling and characterize (in the parlance of genomics) the "antipsychotic transcriptome." In this prospective animal study, broad-scale gene expression profiles were characterized for brains of rats treated with antipsychotics and compared with those of sham controls. We used DNA microarrays containing 8000 sequences to measure the expression patterns of multiple genes in rat fronto-temporo-parietal cortex after intraperitoneal treatment with haloperidol or risperidone. A number of transcripts were differentially expressed between control and treated samples, of which only 36 and 89 were found to significantly differ in expression as a result of exposure to haloperidol or risperidone, respectively (P<0.05). Acutely, 13 genes were more highly expressed and 15 transcripts were found to be significantly less abundant, whereas chronically nine genes were up-regulated and none of them was repressed in haloperidol-treated cortices. Risperidone acutely induced 43 and repressed 46 genes, and chronically over-expressed 6 and down-regulated 11 transcripts. Selected genes were assayed by real-time PCR, then normalized to beta-actin. These assays confirmed the significance of the array results for all transcripts tested. Despite their differing receptor affinity and selectivity, our findings indicate that haloperidol and risperidone interfere with cell survival, neural plasticity, signal transduction, ionic homeostasis and metabolism in a similar manner.

Animals↗

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↗

PubMed2026

PotatoRTD and TomatoRTD: Comprehensive Reference Transcript Datasets for Accurate Transcriptome Analysis and Isoform Discovery.

Transcriptome annotations provide essential information on transcript locations, sequences and structures, including transcription start, end sites and splice junctions. They underpin key biological analyses such as gene and transcript quantification, and the study of transcriptional and post-transcriptional regulation, including alternative transcription initiation, polyadenylation and splicing. Accurate characterisation of transcript isoforms is critical for understanding how gene expression relates to functional protein products. However, for many species-including Solanaceae crops such as potato and tomato-current annotations suffer from limited isoform coverage, with tens or hundreds of thousands of splice junctions and transcript isoforms missing. This undermines the completeness and accuracy of transcript-level analyses. Here, by generating Iso-seq and RNA-seq on a range of tissues and samples, we have produced transcriptome annotations for both potato and tomato with improved coverage, diversity, accurate splice junctions, and transcript start and end sites. We have also made these high-quality resources accessible through genome browsers. These enhanced annotations will enable more accurate transcriptome analyses, supporting higher-resolution and novel biological discoveries.

Solanum tuberosum↗

PubMed2025

Paired Single-Cell Transcriptome and DNA Barcode Detection in Zebrafish Using ScarTrace.

ScarTrace is a CRISPR/Cas9-based genetic lineage tracing method that allows for uniquely barcoding the DNA of single cells at a target GFP sequence during developing zebrafish embryos. Single cells from barcoded adult zebrafish can be isolated from various tissues (e.g., marrow, brain, eyes, fins), and their transcriptome and barcode sequences are captured by single-cell cDNA amplification and genomic DNA nested PCR, respectively. Computationally, cell type and barcode identification permit clone tracing and lineage tree reconstruction of tissues to unravel fate decisions during embryogenesis.

Animals↗

PubMed2026

Uncovering hidden complexity in the Apis mellifera mitotranscriptome: a polyadenylation-centered perspective.

Mitochondrial transcription is gaining increasing attention as researchers seek to better understand the full coding potential of mitochondrial DNA (mtDNA). Emerging evidence suggests that mtDNA may encode additional elements beyond classical oxidative phosphorylation genes, pointing to a more complex transcriptional architecture than previously recognized. In this study, we explored the mitochondrial transcriptome of Apis mellifera (Insecta: Hymenoptera), with a particular focus on polyadenylation-associated features. Our analysis revealed that both sense and antisense transcripts undergo polyadenylation, although transcript abundance and poly(A) tail lengths varied markedly across mitochondrial genes. Several transcripts exhibited alternative isoforms, either extended or truncated, frequently including intergenic regions. These regions may represent functional non-coding elements or structural variants rather than conventional untranslated regions (UTRs). Interestingly, some transcripts also contained non-templated nucleotide additions particularly cytosine residues immediately upstream of the poly(A) tails. Monocistronic units that included portions of downstream intergenic regions were among the most abundantly represented, suggesting a possible regulatory role for these sequences. To experimentally validate our in silico findings, we performed RT-qPCR to assess relative gene expression and applied 3' RACE-PCR to define transcript boundaries. These approaches confirmed the presence of multiple transcript isoforms and supported the involvement of polyadenylation in shaping mitochondrial RNA diversity. Together, our findings reveal a previously underappreciated level of complexity in the A. mellifera mitochondrial transcriptome and highlight the potential regulatory significance of polyadenylation dynamics and intergenic region transcription.

Animals↗

PubMed2005

Tag-based approaches for transcriptome research and genome annotation.

With the increasing number of whole genome sequences available, genomic research has shifted toward the annotation of functional elements and transcribed regions. Thus, the related field of transcriptome research requires accurate methods for the profiling of genes that are not biased by known sequence information, and that also allow for the identification of promoter regions. Starting with serial analysis of gene expression (SAGE), methods making use of short sequencing tags have greatly contributed to transcriptome studies. Here we review recent developments in the use of short sequencing tags in expression profiling, gene discovery and genome annotation. These tags are obtained from the 5' end of mRNAs, both terminal ends of mRNAs, or genomic regions. The 5' end-specific tags, with their ability to identify transcripts along with their transcriptional start sites, will be of particular interest for gene network studies and may become one of the most important approaches in systems biology.

Animals↗

PubMed2006

Transcriptome analysis of Neotyphodium and Epichloë grass endophytes.

Large-scale gene discovery has been performed for the grass fungal endophytes Neotyphodium coenophialum, Neotyphodium lolii, and Epichloë festucae. The resulting sequences have been annotated by comparison with public DNA and protein sequence databases and using intermediate gene ontology annotation tools. Endophyte sequences have also been analysed for the presence of simple sequence repeat and single nucleotide polymorphism molecular genetic markers. Sequences and annotation are maintained within a MySQL database that may be queried using a custom web interface. Two cDNA-based microarrays have been generated from this genome resource. They permit the interrogation of 3806 Neotyphodium genes (Nchip microarray), and 4195 Neotyphodium and 920 Epichloë genes (EndoChip microarray), respectively. These microarrays provide tools for high-throughput transcriptome analysis, including genome-specific gene expression studies, profiling of novel endophyte genes, and investigation of the host grass-symbiont interaction. Comparative transcriptome analysis in Neotyphodium and Epichloë was performed.

Computational Biology↗

PubMed2005

Functional genomic analysis of midgut epithelial responses in Anopheles during Plasmodium invasion.

BACKGROUND: The malaria parasite Plasmodium must complete a complex developmental life cycle within Anopheles mosquitoes before it can be transmitted into the human host. One day after mosquito infection, motile ookinetes traverse the midgut epithelium and, after exiting to its basal site facing the hemolymph, develop into oocysts. Previously, we have identified hemolymph factors that can antagonize or promote parasite development. RESULTS: We profiled on a genomic scale the transcriptional responses of the A. gambiae midgut to P. berghei and showed that more than 7% of the assessed mosquito transcriptome is differentially regulated during invasion. The profiles suggested that actin- and microtubule-cytoskeleton remodeling is a major response of the epithelium to ookinete penetration. Other responses encompass components of innate immunity, extracellular-matrix remodeling, and apoptosis. RNAi-dependent gene silencing identified both parasite antagonists and agonists among regulators of actin dynamics and revealed that actin polymerization is inhibitory to the invading parasite. Combined transcriptional and reverse-genetic analysis further identified an unexpected dual role of the lipid-trafficking machinery of the hemolymph for both parasite and mosquito-egg development. CONCLUSIONS: We conclude that the determinants of malaria-parasite development in Anopheles include components not only of systemic humoral immunity but also of intracellular, local epithelial reactions. These results provide novel mechanistic insights for understanding malaria transmission in the mosquito vector.

Actins↗

PubMed2026

Transcriptome analysis of the pectoral fin degeneration in half-smooth tongue sole (Cynoglossus semilaevis).

Appendage degeneration is a notable morphological feature of some teleosts with specialized benthic lifestyles. The half-smooth tongue sole (Cynoglossus semilaevis) undergoes severe pectoral fin regression during metamorphosis. However, the molecular basis underlying rapid pectoral fin degeneration remains unclear. Here, we performed time-series transcriptome sequencing on pectoral fins at pre-metamorphosis, metamorphosis peak and post-metamorphosis to characterize the molecular changes associated with pectoral fin degeneration. Transcriptional dynamics and functional enrichment showed that no significant enrichment of classical apoptosis-related transcriptional pathways was detected during pectoral fin degeneration. Instead, sustained downregulation of twist1b, identified as a transcriptomic candidate, together with significant upregulation of ssh1, coupled with enrichment of lysosome and ubiquitin-proteasome system (UPS) pathways, suggested enhanced tissue remodeling during pectoral fin degeneration. Temporal expression clustering revealed heterochronic misalignment in the developmental gene expression: upstream initiator tbx5 was upregulated at early metamorphosis, while downstream maintenance signal fgf10 decreased synchronously. Distal patterning gene hoxd12a exhibited premature expression and rapid decay, losing sustained late-phase expression. Moreover, transient elevation of gli3 during metamorphosis may contribute to restricted distal fin growth. We conclude that pectoral fin degeneration in C. semilaevis is associated with heterochronic disruption of developmental signaling and extensive tissue remodeling. This study provides transcriptomic insights into pectoral fin degeneration in tongue soles and establishes a basis for future functional studies of appendage reduction in teleosts.

Animals↗