Tissue-specific Gene Expression Research Articles

Tissue specific tumor-gene link prediction through sampling based GNN using a heterogeneous network.

A tissue sample is a valuable resource for understanding a patient's symptoms and health status in relation to tumor growth. Recent research seeks to establish a connection between tissue-specific tumor samples and genetic markers (genes). This breakthrough has paved the way for personalized cancer therapies. With this motivation, the proposed model constructs a heterogeneous network based on tumor sample-gene relation data and gene-gene interaction data. This network also incorporates tissue-specific gene expression and primary site-based gene counts as features, enabling tissue-specific predictions. Graph neural networks (GNNs) have proven effective in modeling complex interactions and predicting links within this network. The proposed model has successfully predicted tumor-gene associations by leveraging sampling-based GNNs and link layer embedding. The model's performance metrics, such as AUC-ROC scores, reached approximately 94%, demonstrating the potential of this heterogeneous network in predicting tissue-specific tumor sample-gene links. This paper's findings highlight the importance of tissue-specific associations in cancer research.

Evolution of tissue-specific expression of ancestral genes across vertebrates and insects.

Regulation of gene expression is arguably the main mechanism underlying the phenotypic diversity of tissues within and between species. Here we assembled an extensive transcriptomic dataset covering 8 tissues across 20 bilaterian species and performed analyses using a symmetric phylogeny that allowed the combined and parallel investigation of gene expression evolution between vertebrates and insects. We specifically focused on widely conserved ancestral genes, identifying strong cores of pan-bilaterian tissue-specific genes and even larger groups that diverged to define vertebrate and insect tissues. Systematic inferences of tissue-specificity gains and losses show that nearly half of all ancestral genes have been recruited into tissue-specific transcriptomes. This occurred during both ancient and, especially, recent bilaterian evolution, with several gains being associated with the emergence of unique phenotypes (for example, novel cell types). Such pervasive evolution of tissue specificity was linked to gene duplication coupled with expression specialization of one of the copies, revealing an unappreciated prolonged effect of whole-genome duplications on recent vertebrate evolution.

The transcriptome assembly of the European freshwater mussel Unio elongatulus C. Pfeiffer, 1825

Freshwater mussels of the order Unionida are a global conservation concern. Species of this group are strictly freshwater, sessile, slow-growing animals and, extremely sensitive to environmental changes. Human-mediated changes in freshwater habitats are imposing enormous pressure on the survival of freshwater mussels. Although a few flagship species are protected in Europe, other highly imperilled species receive much less attention. Moreover, knowledge about biology, ecology, and evolution and proper conservation assessments of many European species are still sparse. This knowledge gap is further aggravated by the lack of genomic resources available, which are key tools for conservation. Here we present the transcriptome assembly of Unio elongatulus C. Pfeiffer, 1825, one of the least studied European freshwater mussels. Using the individual sequencing outputs from eight physiologically representative mussel tissues, we provide an annotated panel of tissue-specific Relative Gene Expression profiles. These resources are pivotal to studying the species’ biological and ecological features, as well as helping to understand its vulnerability to current and future threats.

Cis-regulatory interfaces reveal the molecular mechanisms underlying the notochord gene regulatory network of Ciona

Tissue-specific gene expression is fundamental in development and evolution, and is mediated by transcription factors and by the cis-regulatory regions (enhancers) that they control. Transcription factors and their respective tissue-specific enhancers are essential components of gene regulatory networks responsible for the development of tissues and organs. Although numerous transcription factors have been characterized from different organisms, the knowledge of the enhancers responsible for their tissue-specific expression remains fragmentary. Here we use Ciona to study the enhancers associated with ten transcription factors expressed in the notochord, an evolutionary hallmark of the chordate phylum. Our results illustrate how two evolutionarily conserved transcription factors, Brachyury and Foxa2, coordinate the deployment of other notochord transcription factors. The results of these detailed cis-regulatory analyses delineate a high-resolution view of the essential notochord gene regulatory network of Ciona, and provide a reference for studies of transcription factors, enhancers, and their roles in development, disease, and evolution.

Olfactory genes affect major depression in highly educated, emotionally stable, lean women: a bridge between animal models and precision medicine

Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.

Evaluation of novel promoters for vascular tissue-specific gene expression in Populus

Due to the extended generation cycle of trees, the breeding process for forest trees tends to be time-consuming. Genetic engineering has emerged as a viable approach to expedite the genetic breeding of forest trees. However, current genetic engineering techniques employed in forest trees often utilize continuous expression promoters such as CaMV 35S, which may result in unintended consequences by introducing genes into non-target tissues. Therefore, it is imperative to develop specific promoters for forest trees to facilitate targeted and precise design and breeding. In this study, we utilized single-cell RNA-Seq data and co-expression network analysis during wood formation to identify three vascular tissue-specific genes in poplar, PP2-A10, PXY, and VNS07, which are expressed in the phloem, cambium/expanding xylem, and mature xylem, respectively. Subsequently, we cloned the promoters of these three genes from ‘84K’ poplar and constructed them into a vector containing the eyGFPuv visual selection marker, along with the 35S mini enhancer to drive GUS gene expression. Transgenic poplars expressing the ProPagPP2-A10::GUS, ProPagPXY::GUS, and ProPagVNS07::GUS constructs were obtained. To further elucidate the tissue specificity of these promoters, we employed qPCR, histochemical staining, and GUS enzyme activity. Our findings not only establish a solid foundation for the future utilization of these promoters to precisely express of specific functional genes in stems but also provide a novel perspective for the modular breeding of forest trees.

Characterization of cinnamate 4-hydroxylase (CYP73A) and p-coumaroyl 3′-hydroxylase (CYP98A) from Leucojum aestivum, a source of Amaryllidaceae alkaloids

Biosynthesis of Amaryllidaceae alkaloids (AA) starts with the condensation of tyramine with 3,4-dihydroxybenzaldehyde. The latter derives from the phenylpropanoid pathway that involves modifications of trans-cinnamic acid, p-coumaric acid, caffeic acid, and possibly 4-hydroxybenzaldehyde, all potentially catalyzed by hydroxylase enzymes. Leveraging bioinformatics, molecular biology techniques, and cell biology tools, this research identifies and characterizes key enzymes from the phenylpropanoid pathway in Leucojum aestivum. Notably, we focused our work on trans-cinnamate 4-hydroxylase (LaeC4H) and p-coumaroyl shikimate/quinate 3ʹ-hydroxylase (LaeC3′H), two key cytochrome P450 enzymes, and on the ascorbate peroxidase/4-coumarate 3-hydroxylase (LaeAPX/C3H). Although LaeAPX/C3H consumed p-coumaric acid, it did not result in the production of caffeic acid. Yeasts expressing LaeC4H converted trans-cinnamate to p-coumaric acid, whereas LaeC3′H catalyzed specifically the 3-hydroxylation of p-coumaroyl shikimate, rather than of free p-coumaric acid or 4-hydroxybenzaldehyde. In vivo assays conducted in planta in this study provided further evidence for the contribution of these enzymes to the phenylpropanoid pathway. Both enzymes demonstrated typical endoplasmic reticulum membrane localization in Nicotiana benthamiana adding spatial context to their functions. Tissue-specific gene expression analysis revealed roots as hotspots for phenylpropanoid-related transcripts and bulbs as hubs for AA biosynthetic genes, aligning with the highest AAs concentration. This investigation adds valuable insights into the phenylpropanoid pathway within Amaryllidaceae, laying the foundation for the development of sustainable production platforms for AAs and other bioactive compounds with diverse applications.

Tapetum-specific expression of cysteine protease induces male sterility in tomato

Male sterile plants play a significant role in developing hybrid varieties to exploit the benefits of hybrid vigour in crops. Cysteine proteases play critical functions, including proteolysis and programmed cell death in plants. In this study, we have generated male-sterile transgenic tomato plants using AdCP (Arachis diogoi cysteine protease) gene under the control of a tapetum-specific promoter (TA-29). The transgenic tomato plants produced non-functional pollen grains. The aborted pollen grains of the male sterile plant did not germinate even after 24 h of incubation compared to normal pollen grains. PCR analysis confirmed the stable integration of transgenes in transgenic plants. Semi-quantitave RT-PCR analysis showed the tissue-specific AdCP gene expression in the anthers of transgenic tomato plants. A back-cross was conducted between the transgenic male-sterile plants (female parent) and control (untransformed) plants (male parent). The T1 progeny indicated the segregation into female fertile and male-sterile plants, showing normal fruit development and seed set. High levels of AdCP transcripts were detected in anther tissues, confirming tapetum-specific expression of the TA29 promoter. The male-sterile tomato plants with targeted expression of the AdCP gene in tapetum could potentially be used to develop novel varieties through hybrid seed production.

Nutri-cereal tissue-specific transcriptome atlas during development: Functional integration of gene expression to identify mineral uptake pathways in little millet (Panicum sumatrense).

Little millet (Panicum sumatrense Roth ex Roem. & Schult.) is an essential minor millet of southeast Asia and Africa's temperate and subtropical regions. The plant is stress-tolerant, has a short life cycle, and has a mineral-rich nutritional profile associated with unique health benefits. We report the developmental gene expression atlas of little millet (genotype JK-8) from ten tissues representing different stages of its life cycle, starting from seed germination and vegetative growth to panicle maturation. The developmental transcriptome atlas led to the identification of 342 827 transcripts. The BUSCO analysis and comparison with the transcriptomes of related species confirm that this study presents high-quality, in-depth coverage of the little millet transcriptome. In addition, the eFP browser generated here has a user-friendly interface, allowing interactive visualizations of tissue-specific gene expression. Using these data, we identified transcripts, the orthologs of which in Arabidopsis and rice are involved in nutrient acquisition, transport, and response pathways. The comparative analysis of the expression levels of these transcripts holds great potential for enhancing the mineral content in crops, particularly zinc and iron, to address the issue of "hidden hunger" and to attain nutritional security, making it a valuable asset for translational research.

Genome wide characterization and expression analysis of CrRLK1L gene family in wheat unravels their roles in development and stress-specific responses.

Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) genes encode a subfamily of receptor-like kinases (RLK) that regulate diverse processes during plant growth, development, and stress responses. The first CrRLK1L was identified from the Catharanthus roseus, commonly known as Madagascar periwinkle. Subsequently, CrRLK1L gene families have been characterized in many plants. The genome of T. aestivum encodes 15 CrRLK1L genes with 43 paralogous copies, with three homeologs each, except for -2-D and -7-A, which are absent. Chromosomal localization analysis revealed a markedly uneven distribution of CrRLK1L genes across seven different chromosomes, with chromosome 4 housing the highest number of genes, while chromosome 6 lacked any CrRLK1L genes. Tissue-specific gene expression analysis revealed distinct expression patterns among the gene family members, with certain members exhibiting increased expression in reproductive tissues. Gene expression analysis in response to various abiotic and biotic stress conditions unveiled differential regulation of gene family members. Cold stress induces CrRLK1Ls -4-B and -15-A while downregulating -3-A and -7B. Drought stress upregulates -9D, contrasting with the downregulation of -7D. CrRLK1L-15-B and -15-D were highly induced in response to 1 hr of heat, and combined drought and heat stress, whereas -10-B is downregulated. Similarly, in response to NaCl stress, only CrRLK1L1 homeologs were induced. Fusarium graminearum and Claviceps purpurea inoculation induces homeologs of CrRLK1L-6 and -7. The analysis of cis-acting elements in the promoter regions identified elements crucial for plant growth and developmental processes. This comprehensive genome-wide analysis and expression study provides valuable insights into the essential functions of CrRLK1L members in wheat.

Abstract 1388: Spatial transcriptome analysis of EMT trait and corresponding immune composition study in HNSCC

Abstract Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignant cancer worldwide. Conventional treatments for this type of cancer involve surgical resection, radiation therapy, and chemotherapy. However, in cases where the tumor recurs or metastasizes distantly, rendering surgical resection or radiation therapy impractical, the only viable option is the utilization of targeted drugs in conjunction with chemotherapy. Despite such interventions, the prognosis remains grim. Hence, the identification of genetic characteristics or biomarkers associated with easy metastasis or recurrence in the early stages of the tumor has become imperative for effective head and neck cancer treatment. The objective of this study is to analyze tumor specimens from the primary site and lymph node metastasis post-surgical resection in HNSCC patients. We employed the GeoMx Digital Spatial Profiler (DSP) for imaging-based digitized gene expression analysis. The DSP provides gene expression information at specific locations we selected, such as the primary tumor center core, primary tumor invasion borders, and lymph node metastasis specimens. The GeoMx DSP spatial analysis tool illustrates the cancer transcriptome atlas (CTA), encompassing the expression of 1825 genes related to cancer and immunity from the primary site to the metastatic site. We identified tissue-specific EMT gene expression patterns in paired tumor regions of interest (ROIs). ITGB1 emerged as the most significant co-expression marker in the primary outer tumor and metastatic tumor. Distinct EMT signature genes expressed in the HNSCC primary site and lymph node metastatic site were also discovered. Additionally, we conducted CTA profiling in correlated stroma ROIs. Through myeloid activity analysis in HNSCC paired samples, we identified distinct myeloid activation signatures in primary and metastatic site stroma cells. These results will provide crucial insights into head and neck cancer treatment strategies based on different tumor site characteristics. Citation Format: Chih-Hung Chung, Muh-Hwa Yang. Spatial transcriptome analysis of EMT trait and corresponding immune composition study in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1388.

Naturally segregating genetic variants contribute to thermal tolerance in a Drosophila melanogaster model system.

Thermal tolerance is a fundamental physiological complex trait for survival in many species. For example, everyday tasks such as foraging, finding a mate, and avoiding predation are highly dependent on how well an organism can tolerate extreme temperatures. Understanding the general architecture of the natural variants within the genes that control this trait is of high importance if we want to better comprehend thermal physiology. Here, we take a multipronged approach to further dissect the genetic architecture that controls thermal tolerance in natural populations using the Drosophila Synthetic Population Resource as a model system. First, we used quantitative genetics and Quantitative Trait Loci mapping to identify major effect regions within the genome that influences thermal tolerance, then integrated RNA-sequencing to identify differences in gene expression, and lastly, we used the RNAi system to (1) alter tissue-specific gene expression and (2) functionally validate our findings. This powerful integration of approaches not only allows for the identification of the genetic basis of thermal tolerance but also the physiology of thermal tolerance in a natural population, which ultimately elucidates thermal tolerance through a fitness-associated lens.

Proteomic Profiling of Messenger Ribonucleoproteins in Mouse Tissues Based on Formaldehyde Cross-Linking.

Messenger ribonucleoprotein particles (mRNPs) are vital for tissue-specific gene expression via mediating posttranscriptional regulations. However, proteomic profiling of proteins in mRNPs, i.e., mRNA-associated proteins (mRAPs), has been challenging at the tissue level. Herein, we report the development of formaldehyde cross-linking-based mRNA-associated protein profiling (FAXRAP), a chemical strategy that enables the identification of mRAPs in both cultured cells and intact mouse organs. Applying FAXRAP, tissue-specific mRAPs were systematically profiled in the mouse liver, kidney, heart, and brain. Furthermore, brain mRAPs in Parkinson's disease (PD) mouse model were investigated, which revealed a global decrease of mRNP assembly in the brain of mice with PD. We envision that FAXRAP will facilitate uncovering the posttranscriptional regulation networks in various biological systems.

Early-life influenza A (H1N1) infection independently programs brain connectivity, HPA AXIS and tissue-specific gene expression profiles

Early-life adversity covers a range of physical, social and environmental stressors. Acute viral infections in early life are a major source of such adversity and have been associated with a broad spectrum of later-life effects outside the immune system or “off-target”. These include an altered hypothalamus–pituitary–adrenal (HPA) axis and metabolic reactions. Here, we used a murine post-natal day 14 (PND 14) Influenza A (H1N1) infection model and applied a semi-holistic approach including phenotypic measurements, gene expression arrays and diffusion neuroimaging techniques to investigate HPA axis dysregulation, energy metabolism and brain connectivity. By PND 56 the H1N1 infection had been resolved, and there was no residual gene expression signature of immune cell infiltration into the liver, adrenal gland or brain tissues examined nor of immune-related signalling. A resolved early-life H1N1 infection had sex-specific effects. We observed retarded growth of males and altered pre-stress (baseline) blood glucose and corticosterone levels at PND42 after the infection was resolved. Cerebral MRI scans identified reduced connectivity in the cortex, midbrain and cerebellum that were accompanied by tissue-specific gene expression signatures. Gene set enrichment analysis confirmed that these were tissue-specific changes with few common pathways. Early-life infection independently affected each of the systems and this was independent of HPA axis or immune perturbations.

A drug stabilizable GAL80ds for conditional control of gene expression via GAL4-UAS and CRISPR-Cas9 systems in Drosophila

The binary GAL4-UAS expression system has been widely used in Drosophila to achieve tissue-specific expression of genes. To further allow for simultaneous spatial and conditional control of gene expression in existing GAL4 expression lines backgrounds, temperature and chemical controllable GAL80 variants have been engineered. Here we add a new drug stabilizable GAL80ds variant, by fusing it to a low-background DHFR-22-DD. We first quantify both single (DD-GAL80) and double (DD-GAL80-DD) architectures and show varied background and activation levels. Next, we demonstrate the utility of GAL80dsDrosophila line to regulate a cell death gene ectopically, in a drug-dependent manner, by utilizing an existing tissue-specific GAL4 driver that regulates the expression of a cell death gene under a UAS. Finally, we showcase the usefulness of GAL80ds in tight drug-mediated regulation of a target gene, from an endogenous locus, by utilizing an existing tissue-specific GAL4 to drive the expression of a dead Cas9 variant fused to the transcriptional coactivator nejire, under a UAS and in gRNA lines. Overall, these new GAL80ds lines expand the use of the wide variety of existing tissue-specific GAL4 and gene-specific gRNA lines. This enables conditional control of genes, both ectopically and endogenously, for a broad array of gene expression control applications.

Ontogeny and tissue specific expression profiles of recombination activating genes (RAGs) during development in Nile tilapia, Oreochromisniloticus

Recombination activating genes (RAGs) mediates the process of rearrangement and somatic recombination (V(D)J) to generate different antibody repertoire. Studies on the expression pattern of adaptive immune genes during ontogenic development are crucial for the formulation of fish immunization strategy. In the present study, Nile tilapia was taken to explore the relative expression profile of RAG genes during their developmental stages. The developmental stages of Nile tilapia, i.e., unfertilized egg, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 and 30 days post-hatch (dph) and kidney, blood, gill, liver and spleen tissues from adult fish were collected and the cDNA synthesis was carried out. Gene specific primers for RAG-1 and RAG-2 of Nile tilapia were designed and their annealing temperature (Tm) was optimized by gradient PCR. Consequently, PCR was performed to confirm the specific amplification of RAG-1 and RAG-2 genes. Quantitative real-time PCR (qRT-PCR) gene expression of RAG-1 and RAG-2 were noticed in all the developmental stages; however, a significant increase was observed after 12 dph and peaked at 24 dph, followed by a gradual decrease until 30 dph. Tissue-specific gene expression profiling revealed that the highest expression of RAG-1 and RAG-2 was observed in the kidney, followed by spleen, gill, liver and blood. The findings of the study explored the suitable timing of lymphoid maturation that could be technically used for the adoption of strategies to improve disease resistance of fish larvae for mitigating larval mortality.

Physiological and Transcriptomic Analyses Reveal the Mechanisms Underlying Methyl Jasmonate-Induced Mannitol Stress Resistance in Banana.

Exogenous methyl jasmonate (MeJA) application has shown promising effects on plant defense under diverse abiotic stresses. However, the mechanisms underlying MeJA-induced stress resistance in bananas are unclear. Therefore, in this study, we treated banana plants with 100 μM MeJA before inducing osmotic stress using mannitol. Plant phenotype and antioxidant enzyme activity results demonstrated that MeJA improved osmotic stress resistance in banana plants. Thereafter, to explore the molecular mechanisms underlying MeJA-induced osmotic stress resistance in banana seedlings, we conducted high-throughput RNA sequencing (RNA-seq) using leaf and root samples of "Brazilian" banana seedlings treated with MeJA for 0 h and 8 h. RNA-seq analysis showed that MeJA treatment upregulated 1506 (leaf) and 3341 (root) genes and downregulated 1768 (leaf) and 4625 (root) genes. Then, we performed gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses on the differentially expressed genes. We noted that linoleic acid metabolism was enriched in both root and leaf samples, and the genes of this pathway exhibited different expression patterns; 9S-LOX genes were highly induced by MeJA in the leaves, whereas 13S-LOX genes were highly induced in the roots. We also identified the promoters of these genes, as the differences in response elements may contribute to tissue-specific gene expression in response to MeJA application in banana seedlings. Overall, the findings of this study provide insights into the mechanisms underlying abiotic stress resistance in banana that may aid in the improvement of banana varieties relying on molecular breeding.

Adipokinetic hormone signaling regulates adult dehydration resistance in the migratory locust

Drought events have become more severe under climate change, and this can pose a major threat to the survival of various organisms. The molecular mechanisms involved in dehydration resistance are not well known. Here, adults of the migratory locust, Locusta migratoria, were subjected to food-mediated dehydration, and adipokinetic hormone (AKH) signaling was found to play a key role in regulating dehydration resistance. Specifically, dehydration shortened the lifespan, increased the body weight loss, and reduced the water loss rate in adult locusts. Global transcriptome profiles revealed variations in tissue-specific gene expression between dehydration-resistant locusts and normal locusts. Importantly, dehydration selection and exposure induced prominent expression of AKH genes in the retrocerebral complex of adult locusts. Furthermore, individual knockdown of AKH1, AKH2, or AKH receptor (AKHR) accelerated water loss and shortened the lifespan of adult locusts under dehydration conditions, and trehalose supplementation ameliorated the negative effects caused by interference with AKH or AKHR. These findings demonstrated that AKH/AKHR signaling-dependent trehalose metabolism plays a crucial role in regulating locust dehydration resistance and thus provide novel insights into the regulatory mechanism underlying drought resistance.

Decoding Non-coding Variants: Recent Approaches to Studying Their Role in Gene Regulation and Human Diseases.

Genome-wide association studies (GWAS) have mapped over 90% of disease- and quantitative-trait-associated variants within the non-coding genome. Non-coding regulatory DNA (e.g., promoters and enhancers) and RNA (e.g., 5' and 3' UTRs and splice sites) are essential in regulating temporal and tissue-specific gene expressions. Non-coding variants can potentially impact the phenotype of an organism by altering the molecular recognition of the cis-regulatory elements, leading to gene dysregulation. However, determining causality between non-coding variants, gene regulation, and human disease has remained challenging. Experimental and computational methods have been developed to understand the molecular mechanism involved in non-coding variant interference at the transcriptional and post-transcriptional levels. This review discusses recent approaches to evaluating disease-associated single-nucleotide variants (SNVs) and determines their impact on transcription factor (TF) binding, gene expression, chromatin conformation, post-transcriptional regulation, and translation.

The genetic regulation of the gastric transcriptome is associated with metabolic and obesity-related traits and diseases.

Tissue-specific gene expression and gene regulation lead to a better understanding of tissue-specific physiology and pathophysiology. We analyzed the transcriptome and genetic regulatory profiles of two distinct gastric sites, corpus and antrum, to identify tissue-specific gene expression and its regulation. Gastric corpus and antrum mucosa biopsies were collected during routine gastroscopies from up to 431 healthy individuals. We obtained genotype and transcriptome data and performed transcriptome profiling and expression quantitative trait locus (eQTL) studies. We further used data from genome-wide association studies (GWAS) of various diseases and traits to partition their heritability and to perform transcriptome-wide association studies (TWAS). The transcriptome data from corpus and antral mucosa highlights the heterogeneity of gene expression in the stomach. We identified enriched pathways revealing distinct and common physiological processes in gastric corpus and antrum. Furthermore, we found an enrichment of the single nucleotide polymorphism (SNP)-based heritability of metabolic, obesity-related, and cardiovascular traits and diseases by considering corpus- and antrum-specifically expressed genes. Particularly, we could prioritize gastric-specific candidate genes for multiple metabolic traits, like NQO1 which is involved in glucose metabolism, MUC1 which contributes to purine and protein metabolism or RAB27B being a regulator of weight and body composition. Our findings show that gastric corpus and antrum vary in their transcriptome and genetic regulatory profiles indicating physiological differences which are mostly related to digestion and epithelial protection. Moreover, our findings demonstrate that the genetic regulation of the gastric transcriptome is linked to biological mechanisms associated with metabolic, obesity-related, and cardiovascular traits and diseases. NEW & NOTEWORTHY We analyzed the transcriptomes and genetic regulatory profiles of gastric corpus and for the first time also of antrum mucosa in 431 healthy individuals. Through tissue-specific gene expression and eQTL analyses, we uncovered unique and common physiological processes across both primary gastric sites. Notably, our findings reveal that stomach-specific eQTLs are enriched in loci associated with metabolic traits and diseases, highlighting the pivotal role of gene expression regulation in gastric physiology and potential pathophysiology.