(meta) transcriptomics
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Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
- MeSH
- celogenomová asociační studie MeSH
- Evropané * genetika MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus genetika MeSH
- kolorektální nádory * genetika MeSH
- lidé MeSH
- multiomika MeSH
- východní Asiaté * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The vast majority of agricultural land undergoes abiotic stress that can significantly reduce agricultural yields. Understanding the mechanisms of plant defenses against stresses and putting this knowledge into practice is, therefore, an integral part of sustainable agriculture. In this review, we focus on current findings in plant resistance to four cardinal abiotic stressors-drought, heat, salinity, and low temperatures. Apart from the description of the newly discovered mechanisms of signaling and resistance to abiotic stress, this review also focuses on the importance of primary and secondary metabolites, including carbohydrates, amino acids, phenolics, and phytohormones. A meta-analysis of transcriptomic studies concerning the model plant Arabidopsis demonstrates the long-observed phenomenon that abiotic stressors induce different signals and effects at the level of gene expression, but genes whose regulation is similar under most stressors can still be traced. The analysis further reveals the transcriptional modulation of Golgi-targeted proteins in response to heat stress. Our analysis also highlights several genes that are similarly regulated under all stress conditions. These genes support the central role of phytohormones in the abiotic stress response, and the importance of some of these in plant resistance has not yet been studied. Finally, this review provides information about the response to abiotic stress in major European crop plants-wheat, sugar beet, maize, potatoes, barley, sunflowers, grapes, rapeseed, tomatoes, and apples.
To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
Nestr.
Motivem tohoto multidisciplinárního výzkumného projektu je získání nových poznatků v oblasti prediktivních a prognostických biomarkerů karcinomu pankreatu, využitelných pro rychlý a ekonomicky výhodný screening pacientů a pro individualizaci jejich léčby. Jedním z cílů je stanovení genetických profilů jednotlivých pacientů s karcinomem slinivky břišní pomocí exomového sekvenování specifických genů karcinogeneze, tedy rozdělení nemocných do úzce definovaných skupin (molekulárních podtypů) s rozdílným biologickým chováním nádoru. Dalším cílem je ověření fenotypového profilu chemorezistence karcinomu pankreatu, zjištěného v našich předchozích studiích na základě analýzy exprese transkriptů a proteinů, a korelace výsledků s jednotlivými molekulárními podtypy. Dílčím cílem je rovněž vyhodnocení mechanismu účinku validovaných biomarkerů pomocí in silico predikcí a funkčních stanovení. Navrhovaný přístup je na mezinárodně konkurenceschopné úrovni a plně v souladu s prioritami 1.7. Vzácná onemocnění a 1.3. Nádorová onemocnění (1.7.2., 2.2.2. a 1.3.2) Programu zdravotnického výzkumu.; The motive of this multidisciplinary research project is to obtain new knowledge in the field of predictive and prognostic biomarkers of pancreatic cancer, usable for rapid and economical screening of patients and for the treatment individualization. One of the aims is to establish the genetic profile of individual patients with pancreatic cancer using exome sequencing of specific genes of carcinogenesis and the division of patients into well-defined subgroups (molecular subtypes) with different biological behavior of the tumor. Another aim is to verify phenotypic profile of chemoresistance of pancreatic cancer observed in our previous studies by the analysis of gene and protein expressions and correlation of the results with different molecular subtypes. Partial aim is also to evaluate the mechanism of action of validated biomarkers using in silico prediction and functional tests. The proposed approach is at internationally competitive levels and fully met the priorities of Program Domains 07.01 Rare diseases and 1.3. Cancer (subdomains 1.7.2., 2.2.2., and 1.3.2).
- MeSH
- chemorezistence MeSH
- fenotyp MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- nádory slinivky břišní diagnóza genetika terapie MeSH
- prognóza MeSH
- sekvenování exomu MeSH
- Check Tag
- lidé MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- onkologie
- gastroenterologie
- genetika, lékařská genetika
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
The Arabidopsis mutant rcd1 is tolerant to methyl viologen (MV). MV enhances the Mehler reaction, i.e. electron transfer from Photosystem I (PSI) to O2, generating reactive oxygen species (ROS) in the chloroplast. To study the MV tolerance of rcd1, we first addressed chloroplast thiol redox enzymes potentially implicated in ROS scavenging. NADPH-thioredoxin oxidoreductase type C (NTRC) was more reduced in rcd1. NTRC contributed to the photosynthetic and metabolic phenotypes of rcd1, but did not determine its MV tolerance. We next tested rcd1 for alterations in the Mehler reaction. In rcd1, but not in the wild type, the PSI-to-MV electron transfer was abolished by hypoxic atmosphere. A characteristic feature of rcd1 is constitutive expression of mitochondrial dysfunction stimulon (MDS) genes that affect mitochondrial respiration. Similarly to rcd1, in other MDS-overexpressing plants hypoxia also inhibited the PSI-to-MV electron transfer. One possible explanation is that the MDS gene products may affect the Mehler reaction by altering the availability of O2. In green tissues, this putative effect is masked by photosynthetic O2 evolution. However, O2 evolution was rapidly suppressed in MV-treated plants. Transcriptomic meta-analysis indicated that MDS gene expression is linked to hypoxic response not only under MV, but also in standard growth conditions. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.
Although the over-expression of angiogenic factors is reported in diffuse large B-cell lymphoma (DLBCL), the poor response to anti-VEGF drugs observed in clinical trials suggests that angiogenesis in these tumours might be driven by VEGF-independent pathways. We show that sphingosine kinase-1 (SPHK1), which generates the potent bioactive sphingolipid sphingosine-1-phosphate (S1P), is over-expressed in DLBCL. A meta-analysis of over 2000 cases revealed that genes correlated with SPHK1 mRNA expression in DLBCL were significantly enriched for tumour angiogenesis meta-signature genes; an effect evident in both major cell of origin (COO) and stromal subtypes. Moreover, we found that S1P induces angiogenic signalling and a gene expression programme that is present within the tumour vasculature of SPHK1-expressing DLBCL. Importantly, S1PR1 functional antagonists, including Siponimod, and the S1P neutralising antibody, Sphingomab, inhibited S1P signalling in DLBCL cells in vitro. Furthermore, Siponimod, also reduced angiogenesis and tumour growth in an S1P-producing mouse model of angiogenic DLBCL. Our data define a potential role for S1P signalling in driving an angiogenic gene expression programme in the tumour vasculature of DLBCL and suggest novel opportunities to target S1P-mediated angiogenesis in patients with DLBCL.
- MeSH
- difúzní velkobuněčný B-lymfom genetika metabolismus patologie MeSH
- endoteliální buňky metabolismus MeSH
- imunohistochemie MeSH
- lidé MeSH
- lysofosfolipidy genetika metabolismus MeSH
- messenger RNA genetika MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- patologická angiogeneze genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- sfingosin analogy a deriváty genetika metabolismus MeSH
- signální transdukce * MeSH
- transkriptom * MeSH
- výpočetní biologie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Hydrogen peroxide (H₂O₂) is steadily gaining more attention in the field of molecular biology research. It is a major REDOX (reduction⁻oxidation reaction) metabolite and at high concentrations induces oxidative damage to biomolecules, which can culminate in cell death. However, at concentrations in the low nanomolar range, H₂O₂ acts as a signalling molecule and in many aspects, resembles phytohormones. Though its signalling network in plants is much less well characterized than are those of its counterparts in yeast or mammals, accumulating evidence indicates that the role of H₂O₂-mediated signalling in plant cells is possibly even more indispensable. In this review, we summarize hydrogen peroxide metabolism in plants, the sources and sinks of this compound and its transport via peroxiporins. We outline H₂O₂ perception, its direct and indirect effects and known targets in the transcriptional machinery. We focus on the role of H₂O₂ in plant growth and development and discuss the crosstalk between it and phytohormones. In addition to a literature review, we performed a meta-analysis of available transcriptomics data which provided further evidence for crosstalk between H₂O₂ and light, nutrient signalling, temperature stress, drought stress and hormonal pathways.
- MeSH
- biologický transport MeSH
- fyziologický stres MeSH
- peroxid vodíku metabolismus MeSH
- regulace genové exprese u rostlin MeSH
- regulátory růstu rostlin genetika metabolismus MeSH
- rostliny genetika metabolismus MeSH
- signální transdukce * MeSH
- transkriptom MeSH
- vývoj rostlin * MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
BACKGROUND: Departures from the standard genetic code in eukaryotic nuclear genomes are known for only a handful of lineages and only a few genetic code variants seem to exist outside the ciliates, the most creative group in this regard. Most frequent code modifications entail reassignment of the UAG and UAA codons, with evidence for at least 13 independent cases of a coordinated change in the meaning of both codons. However, no change affecting each of the two codons separately has been documented, suggesting the existence of underlying evolutionary or mechanistic constraints. RESULTS: Here, we present the discovery of two new variants of the nuclear genetic code, in which UAG is translated as an amino acid while UAA is kept as a termination codon (along with UGA). The first variant occurs in an organism noticed in a (meta)transcriptome from the heteropteran Lygus hesperus and demonstrated to be a novel insect-dwelling member of Rhizaria (specifically Sainouroidea). This first documented case of a rhizarian with a non-canonical genetic code employs UAG to encode leucine and represents an unprecedented change among nuclear codon reassignments. The second code variant was found in the recently described anaerobic flagellate Iotanema spirale (Metamonada: Fornicata). Analyses of transcriptomic data revealed that I. spirale uses UAG to encode glutamine, similarly to the most common variant of a non-canonical code known from several unrelated eukaryotic groups, including hexamitin diplomonads (also a lineage of fornicates). However, in these organisms, UAA also encodes glutamine, whereas it is the primary termination codon in I. spirale. Along with phylogenetic evidence for distant relationship of I. spirale and hexamitins, this indicates two independent genetic code changes in fornicates. CONCLUSIONS: Our study documents, for the first time, that evolutionary changes of the meaning of UAG and UAA codons in nuclear genomes can be decoupled and that the interpretation of the two codons by the cytoplasmic translation apparatus is mechanistically separable. The latter conclusion has interesting implications for possibilities of genetic code engineering in eukaryotes. We also present a newly developed generally applicable phylogeny-informed method for inferring the meaning of reassigned codons.
- MeSH
- buněčné jádro genetika MeSH
- Ciliophora genetika MeSH
- fylogeneze MeSH
- genetický kód * MeSH
- glutamin genetika MeSH
- hmyz parazitologie MeSH
- kodon genetika MeSH
- leucin genetika MeSH
- molekulární evoluce MeSH
- otevřené čtecí rámce genetika MeSH
- Rhizaria genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited. METHODS: Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn's Multiple Comparison and T tests. Kaplan-Meier and log-rank tests were used to determine overall survival. RESULTS: Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples. CONCLUSIONS: Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected.
Immunoglobulin light chain amyloidosis (ALA) is a plasma cell dyscrasia characterized by deposition of amyloid fibrils in various organs and tissues. The current paper is devoted to clarify if ALA has a unique gene expression profile and to its pathogenetic argumentation. The meta-analysis of ALA patients vs. healthy donors, monoclonal gammopathy of undetermined significance, smoldering and multiple myeloma patients' cohorts have revealed molecular signature of ALA consists of 256 genes representing mostly ribosomal proteins and immunoglobulin regions. This signature appears pathogenetically supported and elucidates for the first time the role of ribosome dysfunction in ALA. In summary of our findings with literature overview, we hypothesize that ALA development is associated not only with changes in genes, coding amyloidogenic protein itself, but with post-transcriptional disbalance as well. Based on our data analysis in ALA, ribosome machinery is impaired and the affected link mainly involves translational initiation, elongation and co-translational protein folding.
- MeSH
- amyloidóza genetika MeSH
- geny pro lehké řetězce imunoglobulinů * MeSH
- lidé MeSH
- paraproteinemie genetika MeSH
- stanovení celkové genové exprese MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- dopisy MeSH
- metaanalýza MeSH
- přehledy MeSH
