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Genetics Dec 2015Molecular heterogeneity in human breast cancer has challenged diagnosis, prognosis, and clinical treatment. It is well known that molecular subtypes of breast tumors are...
Molecular heterogeneity in human breast cancer has challenged diagnosis, prognosis, and clinical treatment. It is well known that molecular subtypes of breast tumors are associated with significant differences in prognosis and survival. Assuming that the differences are attributed to subtype-specific pathways, we then suspect that there might be gene regulatory mechanisms that modulate the behavior of the pathways and their interactions. In this study, we proposed an integrated methodology, including machine learning and information theory, to explore the mechanisms. Using existing data from three large cohorts of human breast cancer populations, we have identified an ensemble of 16 master regulator genes (or MR16) that can discriminate breast tumor samples into four major subtypes. Evidence from gene expression across the three cohorts has consistently indicated that the MR16 can be divided into two groups that demonstrate subtype-specific gene expression patterns. For example, group 1 MRs, including ESR1, FOXA1, and GATA3, are overexpressed in luminal A and luminal B subtypes, but lowly expressed in HER2-enriched and basal-like subtypes. In contrast, group 2 MRs, including FOXM1, EZH2, MYBL2, and ZNF695, display an opposite pattern. Furthermore, evidence from mutual information modeling has congruently indicated that the two groups of MRs either up- or down-regulate cancer driver-related genes in opposite directions. Furthermore, integration of somatic mutations with pathway changes leads to identification of canonical genomic alternations in a subtype-specific fashion. Taken together, these studies have implicated a gene regulatory program for breast tumor progression.
Topics: Adult; Breast Neoplasms; Cohort Studies; Disease Progression; Disease-Free Survival; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genes, Regulator; Humans; Machine Learning; Middle Aged; Mutation
PubMed: 26510790
DOI: 10.1534/genetics.115.180125 -
The Turkish Journal of Pediatrics 2023Antiphospholipid syndrome (APS), particularly the catastrophic antiphospholipid syndrome (CAPS), is one of the rare causes of thrombotic microangiopathy (TMA). CAPS is...
BACKGROUND
Antiphospholipid syndrome (APS), particularly the catastrophic antiphospholipid syndrome (CAPS), is one of the rare causes of thrombotic microangiopathy (TMA). CAPS is the most severe form of APS, especially when accompanied by complement dysregulation, causes progressive microvascular thrombosis and failure in multiple organs. In this report, a case of CAPS with TMA accompanied by a genetic defect in the complement system is presented.
CASE
A 13-year-old girl was admitted to the hospital with oliguric acute kidney injury, nephrotic range proteinuria, Coombs positive hemolysis, refractory thrombocytopenia, a low serum complement C3 level and anti-nuclear antibody (ANA) positivity. The kidney biopsy was consistent with TMA. She was first diagnosed with primary APS with clinical and pathological findings and double antibody positivity. As initial treatments, plasmapheresis (PE) was performed and eculizumab was also administered following pulsesteroid and intravenous immunoglobulin treatments. Her renal functions recovered and she was followed up with mycophenolate mofetil, hydroxychloroquine, low dose prednisolone and low molecular weight heparin treatments. The patient presented with severe chest pain, vomiting and acute deterioration of renal functions a few months after the diagnosis of TMA. A CAPS attack was considered due to radiological findings consistent with multiple organ thrombosis and intravenous cyclophosphamide (CYC) was given subsequent to PE. After pulse CYC and PE treatments, her renal functions recovered, she is still being followed for stage-3 chronic kidney disease. Complement factor H-related protein I gene deletion was detected in the genetic study.
CONCLUSIONS
The clinical course of complement mediated CAPS tends to be worse. Complement system dysregulation should be investigated in all CAPS patients, and eculizumab treatment should be kept in mind if detected.
Topics: Female; Humans; Adolescent; Antiphospholipid Syndrome; Thrombotic Microangiopathies; Thrombosis; Genes, Regulator; Mutation
PubMed: 37114699
DOI: 10.24953/turkjped.2022.288 -
Developmental Biology Oct 2007The definitive feature of the many thousand cis-regulatory control modules in an animal genome is their information processing capability. These modules are "wired"... (Review)
Review
The definitive feature of the many thousand cis-regulatory control modules in an animal genome is their information processing capability. These modules are "wired" together in large networks that control major processes such as development; they constitute "genomic computers." Each control module receives multiple inputs in the form of the incident transcription factors which bind to them. The functions they execute upon these inputs can be reduced to basic AND, OR and NOT logic functions, which are also the unit logic functions of electronic computers. Here we consider the operating principles of the genomic computer, the product of evolution, in comparison to those of electronic computers. For example, in the genomic computer intra-machine communication occurs by means of diffusion (of transcription factors), while in electronic computers it occurs by electron transit along pre-organized wires. There follow fundamental differences in design principle in respect to the meaning of time, speed, multiplicity of processors, memory, robustness of computation and hardware and software. The genomic computer controls spatial gene expression in the development of the body plan, and its appearance in remote evolutionary time must be considered to have been a founding requirement for animal grade life.
Topics: Computers; Genes, Regulator; Genome; Models, Genetic; Software
PubMed: 17822690
DOI: 10.1016/j.ydbio.2007.08.009 -
Microbial Cell Factories Jun 2022Trisporic acids are considered to be key regulators of carotenoid biosynthesis and sexual reproduction in zygomycetes, but the mechanisms underlying this regulation have...
BACKGROUND
Trisporic acids are considered to be key regulators of carotenoid biosynthesis and sexual reproduction in zygomycetes, but the mechanisms underlying this regulation have not been fully elucidated.
RESULTS
In this study, the relationships between trisporic acids and lycopene synthesis were investigated in Blakeslea trispora. The lycopene concentration in single fermentation by the (-) strain with the addition of 24 μg/L trisporic acids was slightly higher than that observed in mated fermentation. After transcriptomic analysis, a steroid 5α-reductase-like gene, known as SR5AL in B. trispora, was first reported. 5α-Reductase inhibitors reduced lycopene biosynthesis and downregulated the expression of sex determination and carotenoid biosynthesis genes. Overexpression of the SR5AL gene upregulated these genes, regardless of whether trisporic acids were added.
CONCLUSION
These findings indicated that the SR5AL gene is a key gene associated with the response to trisporic acids.
Topics: Genes, Regulator; Lycopene; Mucorales; Oxidoreductases
PubMed: 35752808
DOI: 10.1186/s12934-022-01853-x -
Scientific Reports Dec 2022The aim of this study is to find those N7-methylguanosine (m7G) methylation-related regulator genes (m7GMRRGs) which were associated with melanoma prognosis and use them...
The aim of this study is to find those N7-methylguanosine (m7G) methylation-related regulator genes (m7GMRRGs) which were associated with melanoma prognosis and use them to develop a prognostic prediction model. Clinical information was retrieved online from The Cancer Gene Atlas (TCGA) and the Gene Expression Omnibus (GEO). R software was used to extract mGMRRGs by differential expression analysis. To create a prognostic risk model, univariate and multivariate Cox regression analyses were employed for the evaluation of the prognostic significance of mG methylation modifiers. Internal validation using cohort from TCGA (training set) and external validation using cohort from GEO (validation set) of the model were carried out. The model's predictive performance was confirmed by using the Kaplan-Meier, univariate, and multivariate Cox regression, and receiver operating characteristic curve (ROC) by constructing column line plots incorporating clinical factor characteristics. Immune infiltration analyses were performed to assess the immune function of mGMRRGs. Drug sensitivity analysis was conducted to study chemotherapeutic drug treatment cues. Prognostic models using four mGMRRGs (EIF4E3, LARP1, NCBP3, and IFIT5) showed good prognostic power in training and validation sets. The area under the curve (AUC) at 1, 3, and 5 years for GEO-melanoma were 0.689, 0.704, and 0.726, respectively. The prediction model could distinctly classify patients with melanoma into different risk subgroups (P < 0.001 for TCGA-melanoma and P < 0.05 for GEO-melanoma). Clinical characteristics were taken into account in Cox regression and AUC analysis, which highlighted that the risk score served as an independent risk factor determining the prognosis of patients with melanoma. Immuno-infiltration analysis showed that mGMRRGs could potentially regulate CD8 T cells as well as regulatory T cells (Treg cells). Results of our study indicate a association between mGMRRGs and melanoma prognosis, and the prognostic prediction model using mGMRRGs may predict the prognosis of patients with melanoma well. Nevertheless, these results may provide a clue for potential better options of melanoma treatment but need further validation in futural studies.
Topics: Humans; CD8-Positive T-Lymphocytes; Prognosis; Biomarkers; Melanoma; Genes, Regulator
PubMed: 36473947
DOI: 10.1038/s41598-022-25698-x -
Trends in Cell Biology Aug 2011Cellular responses often involve a transition of cells from one state to another. A transition from a stem cell to a differentiated cell state, for example, might occur... (Review)
Review
Cellular responses often involve a transition of cells from one state to another. A transition from a stem cell to a differentiated cell state, for example, might occur in response to gene expression changes induced by a transcription factor, or to signaling cascades triggered by a hormone or pathogen. Regulatory networks are thought to control such cellular transitions. Thus, many researchers are interested in reconstructing regulatory networks, not only with the aim of gaining a deeper understanding of cellular transitions, but also of using networks to predict and potentially manipulate cellular transitions and outcomes. In this review, we highlight approaches to the reconstruction of regulatory networks underlying cellular transitions, with special attention to transcriptional regulatory networks. We describe recent regulatory network reconstructions in a variety of organisms, and discuss the success they share in identifying new regulatory components, shared relationships and phenotypic outcomes.
Topics: Animals; Gene Expression Regulation; Gene Regulatory Networks; Genes, Regulator; Humans; Signal Transduction; Stem Cells; Transcription, Genetic
PubMed: 21632251
DOI: 10.1016/j.tcb.2011.05.001 -
Molecular Biology and Evolution Oct 2020We investigated how the two rounds of whole-genome duplication that occurred at the base of the vertebrate lineage have impacted ancient microsyntenic associations...
We investigated how the two rounds of whole-genome duplication that occurred at the base of the vertebrate lineage have impacted ancient microsyntenic associations involving developmental regulators (known as genomic regulatory blocks, GRBs). We showed that the majority of GRBs identified in the last common ancestor of chordates have been maintained as a single copy in humans. We found evidence that dismantling of the duplicated GRB copies occurred early in vertebrate evolution often through the differential retention of the regulatory gene but loss of the bystander gene's exonic sequences. Despite the large evolutionary scale, the presence of duplicated highly conserved noncoding regions provided unambiguous proof for this scenario for multiple ancient GRBs. Remarkably, the dismantling of ancient GRB duplicates has contributed to the creation of large gene deserts associated with regulatory genes in vertebrates, providing a potentially widespread mechanism for the origin of these enigmatic genomic traits.
Topics: Animals; Chromosome Duplication; Evolution, Molecular; Gene Expression Regulation, Developmental; Genes, Regulator; Genome, Human; Humans; Polyploidy; Regulatory Elements, Transcriptional; Vertebrates
PubMed: 32421818
DOI: 10.1093/molbev/msaa123 -
Developmental Biology Jun 2002Gene network analysis requires computationally based models which represent the functional architecture of regulatory interactions, and which provide directly testable... (Review)
Review
Gene network analysis requires computationally based models which represent the functional architecture of regulatory interactions, and which provide directly testable predictions. The type of model that is useful is constrained by the particular features of developmentally active cis-regulatory systems. These systems function by processing diverse regulatory inputs, generating novel regulatory outputs. A computational model which explicitly accommodates this basic concept was developed earlier for the cis-regulatory system of the endo16 gene of the sea urchin. This model represents the genetically mandated logic functions that the system executes, but also shows how time-varying kinetic inputs are processed in different circumstances into particular kinetic outputs. The same basic design features can be utilized to construct models that connect the large number of cis-regulatory elements constituting developmental gene networks. The ultimate aim of the network models discussed here is to represent the regulatory relationships among the genomic control systems of the genes in the network, and to state their functional meaning. The target site sequences of the cis-regulatory elements of these genes constitute the physical basis of the network architecture. Useful models for developmental regulatory networks must represent the genetic logic by which the system operates, but must also be capable of explaining the real time dynamics of cis-regulatory response as kinetic input and output data become available. Most importantly, however, such models must display in a direct and transparent manner fundamental network design features such as intra- and intercellular feedback circuitry; the sources of parallel inputs into each cis-regulatory element; gene battery organization; and use of repressive spatial inputs in specification and boundary formation. Successful network models lead to direct tests of key architectural features by targeted cis-regulatory analysis.
Topics: DNA; Genes, Regulator; Models, Genetic
PubMed: 12027430
DOI: 10.1006/dbio.2002.0617 -
ELife Dec 2021Multidimensional landscapes of regulatory genes in neuronal phenotypes at whole-brain levels in the vertebrate remain elusive. We generated single-cell transcriptomes of...
Multidimensional landscapes of regulatory genes in neuronal phenotypes at whole-brain levels in the vertebrate remain elusive. We generated single-cell transcriptomes of ~67,000 region- and neurotransmitter/neuromodulator-identifiable cells from larval zebrafish brains. Hierarchical clustering based on effector gene profiles ('terminal features') distinguished major brain cell types. Sister clusters at hierarchical termini displayed similar terminal features. It was further verified by a population-level statistical method. Intriguingly, glutamatergic/GABAergic sister clusters mostly expressed distinct transcription factor (TF) profiles ('convergent pattern'), whereas neuromodulator-type sister clusters predominantly expressed the same TF profiles ('matched pattern'). Interestingly, glutamatergic/GABAergic clusters with similar TF profiles could also display different terminal features ('divergent pattern'). It led us to identify a library of RNA-binding proteins that differentially marked divergent pair clusters, suggesting the post-transcriptional regulation of neuron diversification. Thus, our findings reveal multidimensional landscapes of transcriptional and post-transcriptional regulators in whole-brain neuronal phenotypes in the zebrafish brain.
Topics: Animals; Brain; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genes, Regulator; Neurons; Phenotype; Transcriptome; Zebrafish
PubMed: 34895465
DOI: 10.7554/eLife.68224 -
Genetics Jun 2000We show how the phenomena of genetic dominance, overdominance, additivity, and epistasis are generic features of simple diploid gene regulatory networks. These...
We show how the phenomena of genetic dominance, overdominance, additivity, and epistasis are generic features of simple diploid gene regulatory networks. These regulatory network models are together sufficiently complex to catch most of the suggested molecular mechanisms responsible for generating dominant mutations. These include reduced gene dosage, expression or protein activity (haploinsufficiency), increased gene dosage, ectopic or temporarily altered mRNA expression, increased or constitutive protein activity, and dominant negative effects. As classical genetics regards the phenomenon of dominance to be generated by intralocus interactions, we have studied two one-locus models, one with a negative autoregulatory feedback loop, and one with a positive autoregulatory feedback loop. To include the phenomena of epistasis and downstream regulatory effects, a model of a three-locus signal transduction network is also analyzed. It is found that genetic dominance as well as overdominance may be an intra- as well as interlocus interaction phenomenon. In the latter case the dominance phenomenon is intimately connected to either feedback-mediated epistasis or downstream-mediated epistasis. It appears that in the intra- as well as the interlocus case there is considerable room for additive gene action, which may explain to some degree the predictive power of quantitative genetic theory, with its emphasis on this type of gene action. Furthermore, the results illuminate and reconcile the prevailing explanations of heterosis, and they support the old conjecture that the phenomenon of dominance may have an evolutionary explanation related to life history strategy.
Topics: Epistasis, Genetic; Genes, Dominant; Genes, Regulator; Models, Genetic
PubMed: 10835414
DOI: 10.1093/genetics/155.2.969