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The red flour beetle Tribolium castaneum has emerged as a powerful model in insect functional genomics. However, a major limitation in the field is the lack of a detailed spatio-temporal view of the genetic signatures underpinning the function of distinct tissues and life stages. Here, we present an ontogenetic and tissue-specific web-based resource for Tribolium transcriptomics: BeetleAtlas (https://www.beetleatlas.org). This web application provides access to a database populated with quantitative expression data for nine adult and seven larval tissues, as well as for four embryonic stages of Tribolium. BeetleAtlas allows one to search for individual Tribolium genes to obtain values of both total gene expression and enrichment in different tissues, together with data for individual isoforms. To facilitate cross-species studies, one can also use Drosophila melanogaster gene identifiers to search for related Tribolium genes. For retrieved genes there are options to identify and display the tissue expression of related Tribolium genes or homologous Drosophila genes. Five additional search modes are available to find genes conforming to any of the following criteria: exhibiting high expression in a particular tissue; showing significant differences in expression between larva and adult; having a peak of expression at a specific stage of embryonic development; belonging to a particular functional category; and displaying a pattern of tissue expression similar to that of a query gene. We illustrate how the different feaures of BeetleAtlas can be used to illuminate our understanding of the genetic mechanisms underpinning the biology of what is the largest animal group on earth.

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Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder that causes accelerated aging, due to a pathogenic variant in the LMNA gene. This pathogenic results in the production of progerin, a defective protein that disrupts the nuclear lamina's structure. In our study, we conducted a histopathological analysis of various organs in the LmnaG609G/G609G mouse model, which is commonly used to study HGPS. The objective of this study was to show that progerin accumulation drives systemic but organ-specific tissue damage and accelerated aging phenotypes. Our findings show significant fibrosis, inflammation, and dysfunction in multiple organ systems, including the skin, cardiovascular system, muscles, lungs, liver, kidneys, spleen, thymus, and heart. Specifically, we observed severe vascular fibrosis, reduced muscle regeneration, lung tissue remodeling, depletion of fat in the liver, and disruptions in immune structures. These results underscore the systemic nature of the disease and suggest that chronic inflammation and fibrosis play crucial roles in the accelerated aging seen in HGPS. Additionally, our study highlights that each organ responds differently to the toxic effects of progerin, indicating that there are distinct mechanisms of tissue-specific damage.

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Tissue-resident memory CD8+ T cells serve as a first-line defense against many pathogens. In this issue of Immunity, Buquicchio et al. unveil the epigenomic landscapes of virus-specific CD8+ T cell subsets, highlighting common and organ-specific regulators driving their differentiation.

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Family with sequence similarity 161 (Fam161) is an ancient family of microtubule-binding proteins located at the centriole and cilium transition zone (TZ) lumen that exhibit rapid evolution in mice. However, their adaptive role is unclear. Here, we used flies to gain insight into their cell type-specific adaptations. Fam161 is the sole orthologue of FAM161A and FAM161B found in flies. Mutating Fam161 results in reduced male reproduction and abnormal geotaxis behaviour. Fam161 localizes to sensory neuron centrioles and their specialized TZ (the connecting cilium) in a cell type-specific manner, sometimes labelling only the centrioles, sometimes labelling the centrioles and cilium TZ and sometimes labelling the TZ with varying lengths that are longer than other TZ proteins, defining a new ciliary compartment, the extra distal TZ. These findings suggest that Fam161 is an essential centriole and TZ protein with a unique cell type-specific localization in fruit flies that can produce cell type-specific adaptations.

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BACKGROUND: While the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types. RESULTS: Here, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project. We identified age-associated CpG sites (false discovery rate < 0.05) in 8 tissues (all except skeletal muscle, n = 47). This included 162,002 unique hypermethylated and 90,626 hypomethylated CpG sites across all tissue types, with 130,137 (80%) hypermethylated CpGs and 74,703 (82%) hypomethylated CpG sites observed in a single tissue type. While the majority of age-associated CpG sites appeared tissue-specific, the patterns of enrichment among genomic features, such as chromatin states and CpG islands, were similar across most tissues, suggesting common mechanisms underlying cellular aging. Consistent with previous findings, we observed that hypermethylated CpG sites are enriched in regions with repressed polycomb signatures and CpG islands, while hypomethylated CpG sites preferentially occurred in non-CpG islands and enhancers. To gain insights into the functional effects of age-related DNAm changes, we assessed the correlation between DNAm and local gene expression changes to identify age-related expression quantitative trait methylation (age-eQTMs). We identified several age-eQTMs present in multiple tissue-types, including in the CDKN2A, HENMT1, and VCWE regions. CONCLUSION: Overall, our findings will aid future efforts to develop biomarkers of aging and understand mechanisms of aging in diverse human tissue types.

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From eukaryotes to prokaryotes, all cells secrete extracellular vesicles (EVs) as part of their regular homeostasis, intercellular communication, and cargo disposal. Accumulating evidence suggests that small EVs carry functional small RNAs, potentially serving as extracellular messengers and liquid-biopsy markers. Yet, the complete transcriptomic landscape of EV-associated small RNAs during disease progression is poorly delineated due to critical limitations including the protocols used for sequencing, suboptimal alignment of short reads (20-50 nt), and uncharacterized genome annotations-often denoted as the 'dark matter' of the genome. In this study, we investigate the EV-associated small unannotated RNAs that arise from endogenous genes and are part of the genomic 'dark matter', which may play a key emerging role in regulating gene expression and translational mechanisms. To address this, we created a distinct small RNAseq dataset from human prostate cancer & benign tissues, and EVs derived from blood (pre- & post-prostatectomy), urine, and human prostate carcinoma epithelial cell line. We then developed an unsupervised data-based bioinformatic pipeline that recognizes biologically relevant transcriptional signals irrespective of their genomic annotation. Using this approach, we discovered distinct EV-RNA expression patterns emerging from the un-annotated genomic regions (UGRs) of the transcriptomes associated with tissue-specific phenotypes. We have named these novel EV-associated small RNAs as 'EV-UGRs' or "EV-dark matter". Here, we demonstrate that EV-UGR gene expressions are downregulated by ∼100 fold (FDR < 0.05) in the circulating serum EVs from aggressive prostate cancer subjects. Remarkably, these EV-UGRs expression signatures were regained (upregulated) after radical prostatectomy in the same follow-up patients. Finally, we developed a stem-loop RT-qPCR assay that validated prostate cancer-specific EV-UGRs for selective fluid-based diagnostics. Overall, using an unsupervised data driven approach, we investigate the 'dark matter' of EV-transcriptome and demonstrate that EV-UGRs carry tissue-specific Information that significantly alters pre- and post-prostatectomy in the prostate cancer patients. Although further validation in randomized clinical trials is required, this new class of EV-RNAs hold promise in liquid-biopsy by avoiding highly invasive biopsy procedures in prostate cancer.

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BACKGROUND: Many common diseases exhibit uncontrolled mTOR signaling, prompting considerable interest in the therapeutic potential of mTOR inhibitors, such as rapamycin, to treat a range of conditions, including cancer, aging-related pathologies, and neurological disorders. Despite encouraging preclinical results, the success of mTOR interventions in the clinic has been limited by off-target side effects and dose-limiting toxicities. Improving clinical efficacy and mitigating side effects require a better understanding of the influence of key clinical factors, such as sex, tissue, and genomic background, on the outcomes of mTOR-targeting therapies. RESULTS: We assayed gene expression with and without rapamycin exposure across three distinct body parts (head, thorax, abdomen) of D. melanogaster flies, bearing either their native melanogaster mitochondrial genome or the mitochondrial genome from a related species, D. simulans. The fully factorial RNA-seq study design revealed a large number of genes that responded to the rapamycin treatment in a sex-dependent and tissue-dependent manner, and relatively few genes with the transcriptional response to rapamycin affected by the mitochondrial background. Reanalysis of an earlier study confirmed that mitochondria can have a temporal influence on rapamycin response. CONCLUSIONS: We found significant and wide-ranging effects of sex and body part, alongside a subtle, potentially time-dependent, influence of mitochondria on the transcriptional response to rapamycin. Our findings suggest a number of pathways that could be crucial for predicting potential side effects of mTOR inhibition in a particular sex or tissue. Further studies of the temporal response to rapamycin are necessary to elucidate the effects of the mitochondrial background on mTOR and its inhibition.

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The harsh and dry conditions of desert environments have resulted in genomic adaptations, allowing for desert organisms to withstand prolonged drought, extreme temperatures, and limited food resources. Here, we present a comprehensive exploration of gene expression across five tissues (kidney, liver, lung, gastrointestinal tract, and hypothalamus) and 19 phenotypic measurements to explore the whole-organism physiological and genomic response to water deprivation in the desert-adapted cactus mouse (Peromyscus eremicus). The findings encompass the identification of differentially expressed genes and correlative analysis between phenotypes and gene expression patterns across multiple tissues. Specifically, we found robust activation of the vasopressin renin-angiotensin-aldosterone system (RAAS) pathways, whose primary function is to manage water and solute balance. Animals reduced food intake during water deprivation, and upregulation of PCK1 highlights the adaptive response to reduced oral intake via its actions aimed at maintained serum glucose levels. Even with such responses to maintain water balance, hemoconcentration still occurred, prompting a protective downregulation of genes responsible for the production of clotting factors while simultaneously enhancing angiogenesis which is thought to maintain tissue perfusion. In this study, we elucidate the complex mechanisms involved in water balance in the desert-adapted cactus mouse, P. eremicus. By prioritizing a comprehensive analysis of whole-organism physiology and multi-tissue gene expression in a simulated desert environment, we describe the complex response of regulatory processes.

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The pervasiveness of gene expression variation and its contribution to phenotypic variation and evolution is well known. This gene expression variation is context dependent, with differences in regulatory architecture often associated with intrinsic and environmental factors, and is modulated by regulatory elements that can act in cis (linked) or in trans (unlinked) relative to the genes they affect. So far, little is known about how this genetic variation affects the evolution of regulatory architecture among closely related tissues during population divergence. To address this question, we analyzed gene expression in the midgut, hindgut, and Malpighian tubule as well as microbiome composition in the two gut tissues in four Drosophila melanogaster strains and their F1 hybrids from two divergent populations: one from the derived, European range and one from the ancestral, African range. In both the transcriptome and microbiome data, we detected extensive tissue- and genetic background-specific effects, including effects of genetic background on overall tissue specificity. Tissue-specific effects were typically stronger than genetic background-specific effects, although the two gut tissues were not more similar to each other than to the Malpighian tubules. An examination of allele specific expression revealed that, while both cis and trans effects were more tissue-specific in genes expressed differentially between populations than genes with conserved expression, trans effects were more tissue-specific than cis effects. Despite there being highly variable regulatory architecture, this observation was robust across tissues and genetic backgrounds, suggesting that the expression of trans variation can be spatially fine-tuned as well as or better than cis variation during population divergence and yielding new insights into cis and trans regulatory evolution.

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BACKGROUND: The ubiquitously expressed Guanine nucleotide exchange factor, RAPGEF1 (C3G), is essential for early development of mouse embryos. It functions to regulate gene expression and cytoskeletal reorganization, thereby controlling cell proliferation and differentiation. While multiple transcripts have been predicted, their expression in mouse tissues has not been investigated in detail. METHODS & RESULTS: Full length RAPGEF1 isoforms primarily arise due to splicing at two hotspots, one involving exon-3, and the other involving exons 12-14 incorporating amino acids immediately following the Crk binding region of the protein. These isoforms vary in expression across embryonic and adult organs. We detected the presence of unannotated, and unpredicted transcripts with incorporation of cassette exons in various combinations, specifically in the heart, brain, testis and skeletal muscle. Isoform switching was detected as myocytes in culture and mouse embryonic stem cells were differentiated to form myotubes, and embryoid bodies respectively. The cassette exons encode a serine-rich polypeptide chain, which is intrinsically disordered, and undergoes phosphorylation. In silico structural analysis using AlphaFold indicated that the presence of cassette exons alters intra-molecular interactions, important for regulating catalytic activity. LZerD based docking studies predicted that the isoforms with one or more cassette exons differ in interaction with their target GTPase, RAP1A. CONCLUSIONS: Our results demonstrate the expression of novel RAPGEF1 isoforms, and predict cassette exon inclusion as an additional means of regulating RAPGEF1 activity in various tissues and during differentiation.

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Fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of sex and Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to testosterone and Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes, and the role of ADTRP is limited to adipose depots. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex-dependent regulation of human FAHFA metabolism.

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Portability of trans-ancestral polygenic risk scores is often confounded by differences in linkage disequilibrium and genetic architecture between ancestries. Recent literature has shown that prioritizing GWAS SNPs with functional genomic evidence over strong association signals can improve model portability. We leveraged three RegulomeDB-derived functional regulatory annotations-SURF, TURF, and TLand-to construct polygenic risk models across a set of quantitative and binary traits highlighting functional mutations tagged by trait-associated tissue annotations. Tissue-specific prioritization by TURF and TLand provide a significant improvement in model accuracy over standard polygenic risk score (PRS) models across all traits. We developed the Trans-ancestral Iterative Tissue Refinement (TITR) algorithm to construct PRS models that prioritize functional mutations across multiple trait-implicated tissues. TITR-constructed PRS models show increased predictive accuracy over single tissue prioritization. This indicates our TITR approach captures a more comprehensive view of regulatory systems across implicated tissues that contribute to variance in trait expression.

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ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL), and its mutations cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients exhibit cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others previously showed that ABCA1 deficiency causes hyperactivation of the SREBP2 pathway in vitro. Here, we show using Abca1 knockout mice that ABCA1 deficiency leads to tissue-specific dysregulation of SREBP2 activity in a nutritional status-dependent manner, which may underlie the pathophysiology of TD.

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Inbreeding can lead to the accumulation of homozygous single nucleotide polymorphisms (SNPs) in the genome, which can significantly affect gene expression and phenotype. In this study, we examined the impact of homozygous SNPs resulting from inbreeding on alternative polyadenylation (APA) site selection and the underlying genetic mechanisms using inbred Luchuan pigs. Genome resequencing revealed that inbreeding results in a high accumulation of homozygous SNPs within the pig genome. 3' mRNA-seq on leg muscle, submandibular lymph node, and liver tissues was performed to identify differences in APA events between inbred and outbred Luchuan pigs. We revealed different tissue-specific APA usage caused by inbreeding, which were associated with different biological processes. Furthermore, we explored the role of polyadenylation signal (PAS) SNPs in APA regulation under inbreeding and identified key genes such as PUM1, SCARF1, RIPOR2, C1D, and LRRK2 that are involved in biological processes regulation. This study provides resources and sheds light on the impact of genomic homozygosity on APA regulation, offering insights into genetic characteristics and biological processes associated with inbreeding.

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In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function. The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics. We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues. In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.

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MOTIVATION: Although human tissues carry out common molecular processes, gene expression patterns can distinguish different tissues. Traditional informatics methods, primarily at the gene level, overlook the complexity of alternative transcript variants and protein isoforms produced by most genes, changes in which are linked to disease prognosis and drug resistance. RESULTS: We developed TransTEx (Transcript-level Tissue Expression), a novel tissue-specificity scoring method, for grouping transcripts into four expression groups. TransTEx applies sequential cut-offs to tissue-wise transcript probability estimates, subsampling-based P-values and fold-change estimates. Application of TransTEx on GTEx mRNA-seq data divided 199 166 human transcripts into different groups as 17 999 tissue-specific (TSp), 7436 tissue-enhanced, 36 783 widely expressed (Wide), 79 191 lowly expressed (Low), and 57 757 no expression (Null) transcripts. Testis has the most (13 466) TSp isoforms followed by liver (890), brain (701), pituitary (435), and muscle (420). We found that the tissue specificity of alternative transcripts of a gene is predominantly influenced by alternate promoter usage. By overlapping brain-specific transcripts with the cell-type gene-markers in scBrainMap database, we found that 63% of the brain-specific transcripts were enriched in nonneuronal cell types, predominantly astrocytes followed by endothelial cells and oligodendrocytes. In addition, we found 61 brain cell-type marker genes encoding a total of 176 alternative transcripts as brain-specific and 22 alternative transcripts as testis-specific, highlighting the complex TSp and cell-type specific gene regulation and expression at isoform-level. TransTEx can be adopted to the analysis of bulk RNA-seq or scRNA-seq datasets to find tissue- and/or cell-type specific isoform-level gene markers. AVAILABILITY AND IMPLEMENTATION: TransTEx database: https://bmi.cewit.stonybrook.edu/transtexdb/ and the R package is available via GitHub: https://github.com/pallavisurana1/TransTEx.

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BACKGROUND: Tissue-specific analysis of the transcriptome is critical to elucidating the molecular basis of complex traits, but central tissues are often not accessible. We propose a methodology, Multi-mOdal-based framework to bridge the Transcriptome between PEripheral and Central tissues (MOTPEC). METHODS: Multi-modal regulatory elements in peripheral blood are incorporated as features for gene expression prediction in 48 central tissues. To demonstrate the utility, we apply it to the identification of BMI-associated genes and compare the tissue-specific results with those derived directly from surrogate blood. FINDINGS: MOTPEC models demonstrate superior performance compared with both baseline models in blood and existing models across the 48 central tissues. We identify a set of BMI-associated genes using the central tissue MOTPEC-predicted transcriptome data. The MOTPEC-based differential gene expression (DGE) analysis of BMI in the central tissues (including brain caudate basal ganglia and visceral omentum adipose tissue) identifies 378 genes overlapping the results from a TWAS of BMI, while only 162 overlapping genes are identified using gene expression in blood. Cellular perturbation analysis further supports the utility of MOTPEC for identifying trait-associated gene sets and narrowing the effect size divergence between peripheral blood and central tissues. INTERPRETATION: The MOTPEC framework improves the gene expression prediction accuracy for central tissues and enhances the identification of tissue-specific trait-associated genes. FUNDING: This research is supported by the National Natural Science Foundation of China 82204118 (D.Z.), the seed funding of the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the National Institutes of Health (NIH) Genomic Innovator Award R35HG010718 (E.R.G.), NIH/NHGRI R01HG011138 (E.R.G.), NIH/NIA R56AG068026 (E.R.G.), NIH Office of the Director U24OD035523 (E.R.G.), and NIH/NIGMS R01GM140287 (E.R.G.).

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Cytomegalovirus (CMV), a representative member of the Betaherpesvirinae subfamily of herpesviruses, is common in the human population, but immunocompetent individuals are generally asymptomatic when infected with this virus. However, in immunocompromised individuals and immunologically immature fetuses and newborns, CMV can cause a wide range of often long-lasting morbidities and even death. CMV is not only widespread throughout the population but it is also widespread in its hosts, infecting and establishing latency in nearly all tissues and organs. Thus, understanding the pathogenesis of and immune responses to this virus is a prerequisite for developing effective prevention and treatment strategies. Multiple arms of the immune system are engaged to contain the infection, and general concepts of immune control of CMV are now reasonably well understood. Nonetheless, in recent years, tissue-specific immune responses have emerged as an essential factor for resolving CMV infection. As tissues differ in biology and function, so do immune responses to CMV and pathological processes during infection. This review discusses state-of-the-art knowledge of the immune response to CMV infection in tissues, with particular emphasis on several well-studied and most commonly affected organs.

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