INTRODUCTION: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. METHODS AND RESULTS: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. DISCUSSION: Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

• Klíčová slova
• cardiac sympathetic system, coronary arteries, maternal diabetes, mouse model, sympathetic neurons,
• MeSH
• dítě MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• gestační diabetes * metabolismus   MeSH
• kardiovaskulární nemoci * metabolismus   MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• myši MeSH
• novorozenec MeSH
• srdce MeSH
• srdeční selhání * MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• myši MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• Hif1a protein, mouse MeSH Prohlížeč

BACKGROUND: An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals. METHODS: Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses. RESULTS: We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium. CONCLUSIONS: We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.

• Klíčová slova
• Cardiac function, Collagen deposition, Diabetic cardiomyopathy, Inflammation, Sympathetic neurons,
• MeSH
• diabetická kardiomyopatie * genetika   MeSH
• experimentální diabetes mellitus * chemicky indukované   genetika   komplikace   MeSH
• myokard metabolismus   MeSH
• myši MeSH
• srdce inervace   MeSH
• sympatický nervový systém metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Hif1a protein, mouse MeSH Prohlížeč

Catechol-O-methyl transferase (COMT) is involved in detoxification of catechol estrogens, playing cancer-protective role in cells producing or utilizing estrogen. Moreover, COMT suppressed migration potential of breast cancer (BC) cells. To delineate COMT role in metastasis of estrogen receptor (ER) dependent BC, we investigated the effect of COMT overexpression on invasion, transcriptome, proteome and interactome of MCF7 cells, a luminal A BC model, stably transduced with lentiviral vector carrying COMT gene (MCF7-COMT). 2D and 3D assays revealed that COMT overexpression associates with decreased cell invasion (p < 0.0001 for Transwell assay, p < 0.05 for spheroid formation). RNA-Seq and LC-DIA-MS/MS proteomics identified genes associated with invasion (FTO, PIR, TACSTD2, ANXA3, KRT80, S100P, PREX1, CLEC3A, LCP1) being downregulated in MCF7-COMT cells, while genes associated with less aggressive phenotype (RBPMS, ROBO2, SELENBP, EPB41L2) were upregulated both at transcript (|log2FC|> 1, adj. p < 0.05) and protein (|log2FC|> 0.58, q < 0.05) levels. Importantly, proteins driving MET signaling were less abundant in COMT overexpressing cells, and pull-down confirmed interaction between COMT and Kunitz-type protease inhibitor 2 (SPINT2), a negative regulator of MET (log2FC = 5.10, q = 1.04-7). In conclusion, COMT may act as tumor suppressor in ER dependent BC not only by detoxification of catechol estrogens but also by suppressing cell invasion and interplay with MET pathway.

• MeSH
• estrogeny metabolismus   MeSH
• katechol-O-methyltransferasa * genetika   MeSH
• katecholestrogeny MeSH
• katecholy MeSH
• nádory * MeSH
• receptory pro estrogeny metabolismus   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• catechol MeSH Prohlížeč
• estrogeny MeSH
• katechol-O-methyltransferasa * MeSH
• katecholestrogeny MeSH
• katecholy MeSH
• receptory pro estrogeny MeSH

Recent research has already shown that circular RNAs (circRNAs) are functional in gene expression regulation and potentially related to diseases. Due to their stability, circRNAs can also be used as biomarkers for diagnosis. However, the function of most circRNAs remains unknown, and it is expensive and time-consuming to discover it through biological experiments. In this paper, we predict circRNA annotations from the knowledge of their interaction with miRNAs and subsequent miRNA-mRNA interactions. First, we construct an interaction network for a target circRNA and secondly spread the information from the network nodes with the known function to the root circRNA node. This idea itself is not new; our main contribution lies in proposing an efficient and exact deterministic procedure based on the principle of probability-generating functions to calculate the p-value of association test between a circRNA and an annotation term. We show that our publicly available algorithm is both more effective and efficient than the commonly used Monte-Carlo sampling approach that may suffer from difficult quantification of sampling convergence and subsequent sampling inefficiency. We experimentally demonstrate that the new approach is two orders of magnitude faster than the Monte-Carlo sampling, which makes summary annotation of large circRNA files feasible; this includes their reannotation after periodical interaction network updates, for example. We provide a summary annotation of a current circRNA database as one of our outputs. The proposed algorithm could be generalized towards other types of RNA in way that is straightforward.

• Klíčová slova
• Annotation term, Circular RNA, Interaction network,
• MeSH
• biologické markery MeSH
• genové regulační sítě MeSH
• kruhová RNA * MeSH
• messenger RNA genetika   metabolismus   MeSH
• mikro RNA * genetika   metabolismus   MeSH
• pravděpodobnost MeSH
• stanovení celkové genové exprese metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• kruhová RNA * MeSH
• messenger RNA MeSH
• mikro RNA * MeSH

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• buněčná diferenciace * genetika   MeSH
• buněčný rodokmen MeSH
• histondemethylasy MeSH
• lidé MeSH
• meduloblastom * klasifikace   genetika   patologie   MeSH
• metencephalon * embryologie   patologie   MeSH
• mozeček embryologie   patologie   MeSH
• mutace MeSH
• nádory mozečku * klasifikace   genetika   patologie   MeSH
• proteiny hedgehog metabolismus   MeSH
• proteiny T-boxu metabolismus   MeSH
• represorové proteiny MeSH
• svalové proteiny MeSH
• transkripční faktory Otx nedostatek   genetika   MeSH
• transkripční faktory PEBP2A genetika   MeSH
• transkripční faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigen Ki-67 MeSH
• CBFA2T2 myeloid-transforming gene-related protein MeSH Prohlížeč
• CBFA2T3 protein, human MeSH Prohlížeč
• core binding factor alpha MeSH Prohlížeč
• EOMES protein, human MeSH Prohlížeč
• histondemethylasy MeSH
• KDM6A protein, human MeSH Prohlížeč
• OTX2 protein, human MeSH Prohlížeč
• PRDM6 protein, human MeSH Prohlížeč
• proteiny hedgehog MeSH
• proteiny T-boxu MeSH
• represorové proteiny MeSH
• svalové proteiny MeSH
• transkripční faktory Otx MeSH
• transkripční faktory PEBP2A MeSH
• transkripční faktory MeSH

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

• MeSH
• alely MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci genetika   MeSH
• genomika MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• schizofrenie * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

• MeSH
• dítě MeSH
• dospělí MeSH
• genetická variace MeSH
• genové regulační sítě MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• meduloblastom genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory mozečku genetika   MeSH
• předškolní dítě MeSH
• proteiny hedgehog genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• signální transdukce genetika   MeSH
• transkriptom * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• proteiny hedgehog MeSH
• SHH protein, human MeSH Prohlížeč

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

• Klíčová slova
• LncRNAs, autophagy, cancer stem cells (CSCs), haematological malignancies, solid cancers, tumour microenvironment,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones' dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.

• Klíčová slova
• advanced disease, case report, chronic lymphoid leukemia (CLL), disease progression, single-cell RNA-seq (scRNA-seq), therapy resistance,
• Publikační typ
• kazuistiky MeSH

The function of the plant hormone jasmonic acid (JA) in the development of tomato (Solanum lycopersicum) flowers was analyzed with a mutant defective in JA perception (jasmonate-insensitive1-1, jai1-1). In contrast with Arabidopsis (Arabidopsis thaliana) JA-insensitive plants, which are male sterile, the tomato jai1-1 mutant is female sterile, with major defects in female development. To identify putative JA-dependent regulatory components, we performed transcriptomics on ovules from flowers at three developmental stages from wild type and jai1-1 mutants. One of the strongly downregulated genes in jai1-1 encodes the MYB transcription factor SlMYB21. Its Arabidopsis ortholog plays a crucial role in JA-regulated stamen development. SlMYB21 was shown here to exhibit transcription factor activity in yeast, to interact with SlJAZ9 in yeast and in planta, and to complement Arabidopsis myb21-5 To analyze SlMYB21 function, we generated clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR associated protein 9 (Cas9) mutants and identified a mutant by Targeting Induced Local Lesions in Genomes (TILLING). These mutants showed female sterility, corroborating a function of MYB21 in tomato ovule development. Transcriptomics analysis of wild type, jai1-1, and myb21-2 carpels revealed processes that might be controlled by SlMYB21. The data suggest positive regulation of JA biosynthesis by SlMYB21, but negative regulation of auxin and gibberellins. The results demonstrate that SlMYB21 mediates at least partially the action of JA and might control the flower-to-fruit transition. .

• MeSH
• cyklopentany metabolismus   MeSH
• down regulace MeSH
• fenotyp MeSH
• fertilita MeSH
• gibereliny metabolismus   MeSH
• květy genetika   fyziologie   MeSH
• kyseliny indoloctové metabolismus   MeSH
• mutace MeSH
• neplodnost rostlin MeSH
• ovoce genetika   fyziologie   MeSH
• oxylipiny metabolismus   MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• regulace genové exprese u rostlin * MeSH
• regulátory růstu rostlin metabolismus   MeSH
• rostlinné proteiny genetika   metabolismus   MeSH
• Solanum lycopersicum genetika   fyziologie   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vajíčko rostlin genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklopentany MeSH
• gibereliny MeSH
• jasmonic acid MeSH Prohlížeč
• kyseliny indoloctové MeSH
• MYB21 protein, Arabidopsis MeSH Prohlížeč
• oxylipiny MeSH
• proteiny huseníčku MeSH
• regulátory růstu rostlin MeSH
• rostlinné proteiny MeSH
• transkripční faktory MeSH