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PubMed2004

The difficult interpretation of transcriptome data: the case of the GATC regulatory network.

Genomic analyses on part of Escherichia coli's chromosome had suggested the existence of a GATC regulated network. This has recently been confirmed through a transcriptome analysis. Two hypotheses about the molecular control mechanism have been proposed-(i) the GATC network regulation is caused by the presence of GATC clusters within the coding sequences; the regulation is the direct consequence of the clusters' hemi-methylation and therefore their elevated melting temperature, (ii) the regulation is caused by the presence of GATCs in the non-coding 500 bp upstream regions of the affected genes; it is the consequence of an interaction with a regulatory protein like Fnr or CAP. An analysis of the transcriptome data has not allowed us to decide between the two hypotheses. We have therefore taken a classic genomic approach, analyzing the statistical distribution of GATC along the chromosome, using a realistic model of the chromosome as theoretical reference. We observe no particular distribution of GATC in the non-coding upstream regions; however, we confirm the presence of GATC clusters within the genes. In order to verify that the particular distribution observed in E. coli is not a statistical artefact, but has a physiological role, we have carried out the same analysis on Salmonella, making the hypothesis that the genes containing a GATC clusters should be largely the same in the two bacteria. This has been indeed observed, showing that the genes containing a GATC cluster are part of a regulation network. The present is a case study, which demonstrates that the analysis of transcriptome data does not always permit to identify the primary cause of a phenomenon observed; on the other hand, a classic genomic approach linked with a comparative study of related genomes may allow this identification.

Computational Biology↗
PubMed2021

Comparative cellular analysis of motor cortex in human, marmoset and mouse.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Animals↗
PubMed2026

Integrated bulk and single-cell RNA sequencing reveals a prognostic neuro-mimicry signature in papillary thyroid carcinoma.

BACKGROUND: Cancer cells can acquire neuron-like characteristics ("neural mimicry") to promote progression. However, the role of specific ion channel genes in Papillary Thyroid Carcinoma (PTC) and their clinical significance remains unclear. METHODS: We included transcriptomic data from 521 PTC patients in the TCGA cohort. A neuron-specific gene set was used to screen for potential targets. We constructed a prognostic model using LASSO logistic regression. To verify the cellular origin of the signature, we performed single-cell RNA sequencing (scRNA-seq) analysis on the GSE184362 dataset. RESULTS: We established an 8-gene signature involving KCNN4, KCNN1, KCNT2, SNAP25, KCNK16, GABRG1, GABRG2, and GABRB2. The model demonstrated good predictive performance for lymph node metastasis, with an AUC of 0.721 (95% CI 0.677-0.765). Single-cell analysis of seven integrated tumor samples (N = 65,744 cells) confirmed that GABRB2 was specifically enriched in malignant thyrocytes (EPCAM+/KRT18+) at 200-fold higher detection rates than immune cells (20.0% vs. 0.1%, P ≈ 0), supporting tumor-intrinsic neural mimicry. High-risk patients showed immunosuppressive features with altered immune cell infiltration patterns. CONCLUSION: This study identifies a malignant cell-intrinsic signature for predicting PTC prognosis. Validated by single-cell data, our findings suggest that targeting ion channels may represent a potential therapeutic strategy for modulating neuro-immune interactions in thyroid cancer, pending experimental validation.

GABRB2↗
PubMed2003

A general strategy to uncover transcription factor properties identifies a new regulator of drug resistance in yeast.

We demonstrate a genomewide approach to determine the physiological role of a putative transcription factor, Ylr266, identified through yeast genome sequencing program. We constructed activated forms of the zinc finger (Zn(2)Cys(6)) protein Ylr266, and we analyzed the corresponding transcriptomes with DNA microarrays to characterize the up-regulated genes. The direct target genes of Ylr266 were further identified by in vivo chromatin immunoprecipitation procedure. The functions of the genes directly controlled by YLR266c are in agreement with the observed drug-resistance phenotype of the cell expressing an activated form of Ylr266. These target genes code for ATP-binding cassette or major facilitator superfamily transporters such as PDR15, YOR1, or AZR1 or for other proteins such as SNG1, YJL216c, or YLL056c which are already known to be involved in the yeast pleiotropic drug resistance (PDR) phenomenon. YLR266c could thus be named PDR8. Overlaps with the other PDR networks argue in favor of a new specific role for PDR8 in connection with the well known PDR regulators PDR1/PDR3 and YRR1. This strategy to identify the regulatory properties of an anonymous transcription factor is likely to be generalized to all the Zn(2)Cys(6) transcription factors from Saccharomyces cerevisiae and related yeasts.

Drug Resistance, Microbial↗
PubMed2005

Telencephalic embryonic subtractive sequences: a unique collection of neurodevelopmental genes.

The vertebrate telencephalon is composed of many architectonically and functionally distinct areas and structures, with billions of neurons that are precisely connected. This complexity is fine-tuned during development by numerous genes. To identify genes involved in the regulation of telencephalic development, a specific subset of differentially expressed genes was characterized. Here, we describe a set of cDNAs encoded by genes preferentially expressed during development of the mouse telencephalon that was identified through a functional genomics approach. Of 832 distinct transcripts found, 223 (27%) are known genes. Of the remaining, 228 (27%) correspond to expressed sequence tags of unknown function, 58 (7%) are homologs or orthologs of known genes, and 323 (39%) correspond to novel rare transcripts, including 48 (14%) new putative noncoding RNAs. As an example of this latter group of novel precursor transcripts of micro-RNAs, telencephalic embryonic subtractive sequence (TESS) 24.E3 was functionally characterized, and one of its targets was identified: the zinc finger transcription factor ZFP9. The TESS transcriptome has been annotated, mapped for chromosome loci, and arrayed for its gene expression profiles during neural development and differentiation (in Neuro2a and neural stem cells). Within this collection, 188 genes were also characterized on embryonic and postnatal tissue by in situ hybridization, demonstrating that most are specifically expressed in the embryonic CNS. The full information has been organized into a searchable database linked to other genomic resources, allowing easy access to those who are interested in the dissection of the molecular basis of telencephalic development.

Animals↗
PubMed2006

A transcriptomic approach of salinity response in the euryhaline teleost, Dicentrarchus labrax.

Euryhaline teleosts possess the capacity to osmoregulate under various environmental conditions (freshwater to hypersaline water). This physiological capacity is generally monitored using enzyme activity assays (Na+/K+ -ATPase...), hormones quantification (prolactine, growth hormone) or their mRNAs expression. To date, few studies addressed the genetic correlates of adaptation to varying salinity at a molecular level in such fish. In the sea bass Dicentrarchus labrax, genetic differentiation was observed at specific allozyme loci between lagoon- and open-sea populations. In the present study, we investigated transcriptomic response of D. labrax to salt- and freshwater acclimation in two organs involved in osmoregulation, gill and intestine. By using suppression subtractive hybridisation, we characterised 586 partial cDNA sequences encoding proteins potentially involved in the metabolism of sea bass acclimated to salt- or freshwater under experimental conditions. Using these results, we first characterised complete genomic sequence of a carbonic anhydrase and then analysed mRNA expression of genes potentially involved in osmoregulation mechanisms (Na+/K+ -ATPase, carbonic anhydrase, angiotensin-converting enzyme and claudin-3), cell-cycle regulation (secretagogin) and immune system (nephrosin) in gill and intestine of wild fish from open sea and lagoons. Our analyses indicate a strong tissue- and environmental-dependant expression pattern for all the genes studied. A transcriptomic approach such as described in the present paper provides thus a first description of genes involved in metabolic or structural functions important for coping with environmental salinity variations in a euryhaline fish like the common sea bass D. labrax. It should be supplemented by proteomics to check the direct involvement of the gene products at the protein level, and by polymorphism analyses if one is to understand population or individual fluctuations in acclimation to salinity variation.

Adaptation, Physiological↗
PubMed2026

SYT8 Drives Colorectal Cancer Progression and Immune Evasion via the SETD1A-H3K4me3 Axis.

By integrating transcriptomic data from The Cancer Genome Atlas, Gene Expression Omnibus, and a self-established colorectal cancer (CRC) cohort, it was identified that synaptotagmin 8 (SYT8) is significantly up-regulated in tumors and is predictive of poor prognosis. Single-cell RNA sequencing, immunohistochemistry, and immunofluorescence experiments demonstrate that SYT8 expression is largely confined to tumor cells, predominantly in the nucleus. Functional assays reveal that depletion of SYT8 impairs, whereas its overexpression enhances, CRC cell proliferation and invasion. Transcriptomic profiling indicates an enrichment of cell cycle and epithelial-mesenchymal transition signatures. Mechanistically, co-immunoprecipitation/mass spectrometry identifies SET domain containing 1A (SETD1A) as a direct SYT8-interacting partner. The SYT8-SETD1A axis forms a positive-feedback loop that increases histone H3 lysine 4 trimethylation (H3K4me3) levels and drives the transcription of protumorigenic genes. Immune profiling further indicates that high SYT8 expression correlates with increased regulatory T-cell infiltration, suggesting an immunosuppressive microenvironment and potential resistance to immunotherapy. Collectively, SYT8 promotes CRC progression through the SETD1A/H3K4me3-mediated activation of the cell cycle, induction of epithelial-mesenchymal transition, and remodeling of the immune microenvironment. Therefore, SYT8 is established as a prognostic biomarker and serves as a therapeutic target in colorectal cancer.

Humans↗
PubMed2002

Analysis of transcriptomes of human malaria parasite Plasmodium falciparum using full-length enriched library: identification of novel genes and diverse transcription start sites of messenger RNAs.

Now that the sequencing of the complete genome of the human malaria parasite Plasmodium falciparum is now underway, importance of analyses of complementary DNAs (cDNAs) is looming up. We constructed a full-length-enriched cDNA library from erythrocytic stage P. falciparum using the 'oligo-capping' method (Nucleic Acids Res. 29 (2001) 70). In this report we describe the novel genes identified using this library and detailed characterization of transcriptional start site of knob-associated histidine rich protein gene. Contrary to the previous report we conclude all the transcripts of plasmodium genes have diverse start sites. Sequence comparisons between the cDNAs and the complete sequences of chromosomes 2 identified three novel genes that had been missed by computational predictions. Moreover, analysis of transcriptional start sites revealed that the average length of the 5' untranslated region was 346 nt, which is much longer than that in humans. The transcriptional start sites of all the genes studied were far more diverse than those of human genes. These observations may reflect unique mechanism(s) of gene expression in this organism, which has an extremely AT-rich genome.

5' Untranslated Regions↗
PubMed2026

Genome-wide association studies of plant traits and functional analysis of leaf development-related genes in citrus.

Labor-saving and high-light-efficiency tree architecture is a key breeding objective for woody fruit trees like citrus. However, population genetics information on these traits remains limited. In this study, tree architecture, thorn, and leaf traits were evaluated in 353 F2 progeny derived from a cross between Clementine mandarin and precocious trifoliate orange-an early-flowering variety. A random subset of 300 offspring was sequenced for a genome-wide association study (GWAS), which detected 10 216 significantly associated SNPs and defined several major quantitative trait loci (QTLs) for the target traits. Subsequent bulked segregant analysis (BSA) and GWAS on individuals with extreme compound leaf phenotypes mapped the causal gene(s) to a 0.8 Mb region (22.15-22.95 Mb) on chromosome 4. Genetic analysis across multiple hybrid combinations confirmed that the compound leaf trait in trifoliate orange is dominantly inherited and follows Mendelian segregation. Transcriptome profiling of parental leaves at different developmental stages identified a KNOX gene, CiKNAT6, as a candidate. Further validation using CAPS markers and Hi-Tom sequencing demonstrated tight linkage between an InDel polymorphism in CiKNAT6 and leaf shape across diverse citrus species and the F2 population, with co-segregation observed for the compound leaf trait. Due to alternative splicing producing seven splice variants, the CiKNAT6 DNA sequence was selected for genetic transformation experiments. Functional analysis revealed that the Clementine mandarin allele of CiKNAT6 is non-functional owing to an InDel, whereas ectopic expression of the trifoliate orange allele in tobacco and lemon induced leaf curling and reduced leaf size. CRISPR-Cas9 knockout of CiKNAT6 in trifoliate orange resulted in increased leaf area. These findings provide valuable genetic resources and insights for future studies on tree architecture and leaf morphology.

Plant Leaves↗
PubMed2026

Volumetric DNA microscopy for mapping spatial transcriptomes in three dimensions.

The architecture and function of biological systems are inherently three-dimensional, yet most existing spatial transcriptomic technologies remain restricted to thin tissue sections, limiting their capacity to resolve cellular organization and microenvironments within intact tissue volumes. To address this limitation, we developed volumetric DNA microscopy, a scalable, optics-free approach for spatial transcriptome profiling directly within intact biological specimens. The method encodes spatial information into DNA molecules that form a dense intermolecular network in situ, enabling the reconstruction of three-dimensional spatial relationships through short-read sequencing and computational analysis. Here we detail the complete workflow including in situ cDNA synthesis, spatial encoding through DNA nanoball formation, dual-scale proximity bridging between neighboring nanoballs and spatial reconstruction via geodesic spectral embedding. Sequencing libraries can be generated within 7-8 d by a competent graduate-level molecular biologist, followed by standardized downstream computational analysis. Because the workflow requires only routine molecular biology reagents and a benchtop sequencer, volumetric DNA microscopy provides a versatile platform for exploring genetic and morphological features in intact tissues.

Spatial Transcriptomics↗
PubMed2005

Sexually dimorphic gene expression in the hypothalamus, pituitary gland, and cortex.

We examined sex differences in the transcriptomes of hypothalamus, pituitary gland, and cortex of male and female mice using serial analysis of gene expression. In total 940,669 tags were sequenced. In hypothalamus, 3 transcripts are differentially expressed by gender, including growth hormone (neuromodulation) and 3beta-hydroxysteroid dehydrogenase-1 (steroidogenesis). In pituitary gland, 43 transcripts are differentially expressed, including RAS guanyl-releasing protein 2 (cell signaling), ornithine transporter (mitochondrial transport), H3 histone family 3B (chromatin structure), heterogeneous nuclear ribonucleoprotein U (chromatin remodeling), NADH dehydrogenase (mitochondrial oxidative phosphorylation), neuronatin (cell differentiation), and ribosomal protein S27a (protein metabolism). EST X (inactive)-specific transcript antisense is expressed at a higher level in the three female organs, whereas growth hormone and NADH dehydrogenase are expressed at higher levels in female cortex. Thus, the current study has characterized key sexual dimorphisms in the transcriptomes of the hypothalamus, pituitary, and cortex.

Animals↗
PubMed2005

Contribution of transcriptional regulation to natural variations in Arabidopsis.

BACKGROUND: Genetic control of gene transcription is a key component in genome evolution. To understand the transcriptional basis of natural variation, we have studied genome-wide variations in transcription and characterized the genetic variations in regulatory elements among Arabidopsis accessions. RESULTS: Among five accessions (Col-0, C24, Ler, WS-2, and NO-0) 7,508 probe sets with no detectable genomic sequence variations were identified on the basis of the comparative genomic hybridization to the Arabidopsis GeneChip microarray, and used for accession-specific transcriptome analysis. Two-way ANOVA analysis has identified 60 genes whose mRNA levels differed in different accession backgrounds in an organ-dependent manner. Most of these genes were involved in stress responses and late stages of plant development, such as seed development. Correlation analysis of expression patterns of these 7,508 genes between pairs of accessions identified a group of 65 highly plastic genes with distinct expression patterns in each accession. CONCLUSION: Genes that show substantial genetic variation in mRNA level are those with functions in signal transduction, transcription and stress response, suggesting the existence of variations in the regulatory mechanisms for these genes among different accessions. This is in contrast to those genes with significant polymorphisms in the coding regions identified by genomic hybridization, which include genes encoding transposon-related proteins, kinases and disease-resistance proteins. While relatively fewer sequence variations were detected on average in the coding regions of these genes, a number of differences were identified from the upstream regions, several of which alter potential cis-regulatory elements. Our results suggest that nucleotide polymorphisms in regulatory elements of genes encoding controlling factors could be primary targets of natural selection and a driving force behind the evolution of Arabidopsis accessions.

Arabidopsis↗
PubMed2025

NMFProfiler: a multi-omics integration method for samples stratified in groups.

MOTIVATION: The development of high-throughput sequencing enabled the massive production of "omics" data for various applications in biology. By analyzing simultaneously paired datasets collected on the same samples, integrative statistical approaches allow researchers to get a global picture of such systems and to highlight existing relationships between various molecular types and levels. Here, we introduce NMFProfiler, an integrative supervised NMF that accounts for the stratification of samples into groups of biological interest. RESULTS: NMFProfiler was shown to successfully extract signatures characterizing groups with performances comparable to or better than state-of-the-art approaches. In particular, NMFProfiler was used in a clinical study on atopic dermatitis (AD) and to analyze a multi-omic cancer dataset. In the first case, it successfully identified signatures combining known AD protein biomarkers and novel transcriptomic biomarkers. In addition, it was also able to extract signatures significantly associated to cancer survival. AVAILABILITY AND IMPLEMENTATION: NMFProfiler is released as a Python package, NMFProfiler (v0.3.0), available on PyPI.

Humans↗
PubMed2026

Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.

TECPR2 is a key regulator of autophagy, encoded by the TECPR2 gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report a teenage female with a syndromic intellectual disability disorder associated with neuromuscular abnormalities. Multi-omics analysis including genomics, transcriptomics, and proteomics, together with muscle biopsy from the affected individual, were used in this clinical case. Through trio exome sequencing we identified two heterozygous variants in the TECPR2 gene, NM_014844.4: c.480G>A; p.(Gln160=) and c.2846C>A; p.(Ala949Glu). Both were classified as variants of uncertain significance due to the lack of supporting evidence for pathogenicity. Subsequent long-read sequencing phased the variants and confirmed they were in trans. Additional functional studies using RNAseq and proteomics analyses verified the pathogenicity of the variants. This case study demonstrated the value of a multi-omics assisted analysis, which complemented the traditional phenotype-first approach in reaching a definitive clinical diagnosis.

Humans↗
PubMed2005

Genome complexity and repetitive DNA in metazoans from extreme marine environments.

As genomics converges with ecology and evolution to identify the fundamental linkages between genome structure and function, genome and transcriptome complexity will need to be measured in organisms from more diverse habitats, most often in the absence of complete sequence data. Here, we describe the complexity of ten genomes measured by a novel, high-throughput fluorescence-based kinetic hybridization assay. We applied the Shannon information index, H, and a related, fluorescence-adjusted index, H(f), as unique metrics of the hybridization kinetics to complement the conventional rate constant, k. A strong, positive relationship was present between H(f), and the repetitive DNA content of five eukaryotic genomes previously determined by Cot kinetic analyses (Onchorynchus keta, Ilyanassa obsoleta, Bos taurus, Limulus polyphemus, Saccharyomyces cerevisiae). This relationship was used to characterize the complexity of previously unstudied genomic samples in five metazoan taxa from three marine environments, including deep-sea hydrothermal vents (Alvinella pompejana), the temperate subtidal (Streblospio benedicti), and Antarctic coastal bays (Sterechinus neumayeri, Odontaster validus, Tritonia antarctica). Contrary to the predictions of nucleotypic theory, Antarctic invertebrates consistently had the lowest quantities of repetitive DNA in conjunction with low metabolic rates and highly protracted rates of cell division and larval development. Conversely, hydrothermal vent species with rapid cell division and growth do not have significantly different genome sizes or particularly low amounts of repetitive DNA as compared to non-vent, deep-sea taxa. Furthermore, there appears to be a positive correlation between the temperature at which the most abundant repetitive sequence classes anneal and habitat thermal stability. Thus, our study reveals a potential shift in repetitive sequence representation between these extreme environments that may be related to genome function in species living at these different thermal regimes.

Animals↗
PubMed2026

Genomic and transcriptomic quality control for an autologous iPSC-derived cell therapy for Parkinson's disease.

Toward development of an autologous, induced pluripotent stem cell (iPSC)-based cell therapy for Parkinson's disease (PD), we demonstrate successful, reproducible genomic and transcriptomic qualification of patient-derived dopaminergic neuron precursor cells (DANPCs) across multiple donors. Our analysis includes whole-genome sequencing data from fibroblasts, iPSCs, and DANPCs and the development of NeuriTest, an RNAseq-based bioinformatic analysis of DANPCs designed to predict cell quality based on empirical animal data. Autologous cell therapies are immune matched to the patient, potentially augmenting durability of benefit compared to allogeneic cells while negating the need for immunosuppression and accompanying side effects. Patient-specific iPSCs are an autologous cell source that can be differentiated to dopaminergic neurons, the cell type lost in PD. We report here our preclinical manufacturing strategy and results demonstrating efficacy in a PD rodent model and safety in a 9-month GLP toxicology study.

Parkinson’s disease↗
PubMed2005

Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function.

The mammalian transcriptome contains many non-protein-coding RNAs (ncRNAs), but most of these are of unclear significance and lack strong sequence conservation, prompting suggestions that they might be non-functional. However, certain long functional ncRNAs such as Air and Xist are also poorly conserved. In this article, we systematically analyzed the conservation of several groups of functional ncRNAs, including miRNAs, snoRNAs and longer ncRNAs whose function has been either documented or confidently predicted. As expected, miRNAs and snoRNAs were highly conserved. By contrast, the longer functional non-micro, non-sno ncRNAs were much less conserved with many displaying rapid sequence evolution. Our findings suggest that longer ncRNAs are under the influence of different evolutionary constraints and that the lack of conservation displayed by the thousands of candidate ncRNAs does not necessarily signify an absence of function.

Animals↗
PubMed2005

The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans.

The evolutionary importance of gene-expression divergence is unclear: some studies suggest that it is an important mechanism for evolution by natural selection, whereas others claim that most between-species regulatory changes are neutral or nearly neutral. We examined global transcriptional divergence patterns in a set of Caenorhabditis elegans mutation-accumulation lines and natural isolate lines to provide insights into the evolutionary importance of transcriptional variation and to discriminate between the forces of mutation and natural selection in shaping the evolution of gene expression. We detected the effects of selection on transcriptional divergence patterns and characterized them with respect to coexpressed gene sets, chromosomal clustering of expression changes and functional gene categories. We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences.

Animals↗