Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases, which are broadly expected to lead to the identification of new drug targets and ...opportunities for treatment. Drug development, however, remains hampered by the time taken and costs expended to achieve regulatory approval, leading many clinicians and researchers to consider alternative paths to more immediate clinical outcomes. In this Review, we explore approaches that leverage common variant genetics to identify opportunities for repurposing existing drugs, also known as drug repositioning. These approaches include the identification of compounds by linking individual loci to genes and pathways that can be pharmacologically modulated, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization, and polygenic scoring.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Gene expression is precisely controlled in a stage and cell-type-specific manner, largely through the interaction between cis-regulatory elements and their associated trans-acting factors. Where ...these components aggregate in promoters and enhancers, they are able to cooperate to modulate chromatin structure and support the engagement in long-range 3D superstructures that shape the dynamics of a cell's genomic architecture. Recently, the term 'super-enhancer' has been introduced to describe a hyper-active regulatory domain comprising a complex array of sequence elements that work together to control the key gene networks involved in cell identity. Here, we survey the unique characteristics of super-enhancers compared to other enhancer types and summarize the recent advances in our understanding of their biological role in gene regulation. In particular, we discuss their capacity to attract the formation of phase-separated condensates, and capacity to generate three-dimensional genome structures that precisely activate their target genes. We also propose a multi-stage transition model to explain the evolutionary pressure driving the development of super-enhancers in complex organisms, and highlight the potential for involvement in tumorigenesis. Finally, we discuss more broadly the role of super-enhancers in human health disorders and related potential in therapeutic interventions.
Abstract Psychiatric syndromes, including schizophrenia, mood disorders, and autism spectrum disorders, are characterized by a complex range of symptoms, including psychosis, depression, mania, and ...cognitive deficits. Although the mechanisms driving pathophysiology are complex and remain largely unknown, advances in the understanding of gene association and gene networks are providing significant clues to their etiology. In recent years, small noncoding RNA molecules known as microRNA (miRNA) have emerged as potential players in the pathophysiology of mental illness. These small RNAs regulate hundreds of target transcripts by modifying their stability and translation on a broad scale, influencing entire gene networks in the process. There is evidence to suggest that numerous miRNAs are dysregulated in postmortem neuropathology of neuropsychiatric disorders, and there is strong genetic support for association of miRNA genes and their targets with these conditions. This review presents the accumulated evidence linking miRNA dysregulation and dysfunction with schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorders and the potential of miRNAs as biomarkers or therapeutics for these disorders. We further assess the functional roles of some outstanding miRNAs associated with these conditions and how they may be influencing the development of psychiatric symptoms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
microRNAs (miRNAs) are small endogenous non-coding RNAs that function as the universal specificity factors in post-transcriptional gene silencing. Discovering miRNAs, identifying their targets and ...further inferring miRNA functions have been a critical strategy for understanding normal biological processes of miRNAs and their roles in the development of disease. In this review, we focus on computational methods of inferring miRNA functions, including miRNA functional annotation and inferring miRNA regulatory modules, by integrating heterogeneous data sources. We also briefly introduce the research in miRNA discovery and miRNA-target identification with an emphasis on the challenges to computational biology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The developmental processes that establish the synaptic architecture of the brain while retaining capacity for activity-dependent remodeling, are complex and involve a combination of genetic and ...epigenetic influences. Dysregulation of these processes can lead to problems with neural circuitry which manifest in humans as a range of neurodevelopmental syndromes, such as schizophrenia, bipolar disorder and fragile X mental retardation. Recent studies suggest that prenatal, postnatal and intergenerational environmental factors play an important role in the aetiology of stress-related psychopathology. A number of these disorders have been shown to display epigenetic changes in the postmortem brain that reflect early life experience. These changes affect the regulation of gene expression though chromatin remodeling (transcriptional) and post-transcriptional influences, especially small noncoding microRNA (miRNA). These dynamic and influential molecules appear to play an important function in both brain development and its adaption to stress. In this review, we examine the role of miRNA in mediating the brain's response to both prenatal and postnatal environmental perturbations and explore how stress- induced alterations in miRNA expression can regulate the stress response via modulation of the immune system. Given the close relationship between environmental stress, miRNA, and brain development/function, we assert that miRNA hold a significant position at the molecular crossroads between neural development and adaptations to environmental stress. A greater understanding of the dynamics that mediate an individual's predisposition to stress-induced neuropathology has major human health benefits and is an important area of research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Schizophrenia is a complex neuropsychiatric disorder that involves disturbances in neural circuitry and synaptic function. The exquisite network architecture and capacity for discreet ...post-synaptic remodeling of neurons requires coordination by an elaborate intracellular network of molecular signal transduction systems. The redundancy of these networks means that many combinations of gene variants have the potential to cause system dysfunction that manifest as related neurobehavioural syndromes. Recent investigation has revealed that posttranscriptional gene regulation and associated small non-coding microRNA (miRNA), are likely to be important factors shaping the topography of these networks. miRNA display complex temporospatial expression patterns in the mammalian brain and have the potential to regulate thousands of target genes by functioning as the specificity factor for intracellular gene-silencing machinery. They are emerging as key regulators of many neurodevelopmental and neurological processes as their dysregulation could lead to pervasive changes in the network structure during development and in the mature brain that are highly significant in the pathophysiology of schizophrenia. This review looks at mounting evidence that mature miRNA levels are altered in both the cerebral cortex and peripheral blood mononuclear cells (PBMCs) in schizophrenia. It also examines compelling evidence that the underlying miRNA biogenesis machinery and miRNA genes themselves are subject to disease-associated genetic mutation and epigenetic influence. Significantly, these changes in miRNA expression and associated machinery may represent new targets for pharmaceutical development, and the identification of miRNA signatures in PBMCs suggest that miRNA biomarkers of schizophrenia may also provide the basis for new clinical diagnostics. These developments have tremendous potential and highlight the significance of this avenue of research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Schizophrenia is a severe psychiatric disorder with a complex array of signs and symptoms that causes very significant disability in young people. While schizophrenia has a strong genetic component, ...with heritability around 80%, there is also a very significant range of environmental exposures and stressors that have been implicated in disease development and neuropathology, such as maternal immune infection, obstetric complications, childhood trauma and cannabis exposure. It is postulated that epigenetic factors, as well as regulatory non-coding RNAs, mediate the effects of these environmental stressors. In this review, we explore the most well-known epigenetic marks, including DNA methylation and histone modification, along with emerging RNA mediators of epigenomic state, including miRNAs and lncRNAs, and discuss their collective potential for involvement in the pathophysiology of schizophrenia implicated through the postmortem analysis of brain tissue. Given that peripheral tissues, such as blood, saliva, and olfactory epithelium have the same genetic composition and are exposed to many of the same environmental exposures, we also examine some studies supporting the application of peripheral tissues for epigenomic biomarker discovery in schizophrenia. Finally, we provide some perspective on how these biomarkers may be utilized to capture a signature of past events that informs future treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Rapid input-restricted change in gene expression is an important aspect of synaptic plasticity requiring complex mechanisms of post-transcriptional mRNA trafficking and regulation. Small non-coding ...miRNA are uniquely poised to support these functions by providing a nucleic-acid-based specificity component for universal-sequence-dependent RNA binding complexes. We investigated the subcellular distribution of these molecules in resting and potassium chloride depolarized human neuroblasts, and found both selective enrichment and depletion in neurites. Depolarization was associated with a neurite-restricted decrease in miRNA expression; a subset of these molecules was recovered from the depolarization medium in nuclease resistant extracellular exosomes. These vesicles were enriched with primate specific miRNA and the synaptic-plasticity-associated protein MAP1b. These findings further support a role for miRNA as neural plasticity regulators, as they are compartmentalized in neurons and undergo activity-associated redistribution or release into the extracellular matrix.
SeqGSEA is an open-source Bioconductor package for the functional integration of differential expression and splicing analysis in RNA-Seq data. SeqGSEA implements an analysis pipeline, which first ...computes differential splicing and differential expression scores, followed by integrating them into a per-gene score that quantifies each gene's association with a phenotype of interest, and finally executes gene set enrichment analysis in a cutoff-free manner to achieve biological insights. SeqGSEA accounts for biological variability and determines the statistical significance of gene pathways and networks using subject permutation, and thus requires at least five samples per group. Real applications show that SeqGSEA detects more biologically meaningful gene sets without biases toward long or highly expressed genes. SeqGSEA can be set up to run in parallel to reduce the analysis time.
The SeqGSEA package with a vignette is available at http://bioconductor.org/packages/release/bioc/html/SeqGSEA.html.
RNA-Seq has become a key technology in transcriptome studies because it can quantify overall expression levels and the degree of alternative splicing for each gene simultaneously. To interpret ...high-throughout transcriptome profiling data, functional enrichment analysis is critical. However, existing functional analysis methods can only account for differential expression, leaving differential splicing out altogether.
In this work, we present a novel approach to derive biological insight by integrating differential expression and splicing from RNA-Seq data with functional gene set analysis. This approach designated SeqGSEA, uses count data modelling with negative binomial distributions to first score differential expression and splicing in each gene, respectively, followed by two strategies to combine the two scores for integrated gene set enrichment analysis. Method comparison results and biological insight analysis on an artificial data set and three real RNA-Seq data sets indicate that our approach outperforms alternative analysis pipelines and can detect biological meaningful gene sets with high confidence, and that it has the ability to determine if transcription or splicing is their predominant regulatory mechanism.
By integrating differential expression and splicing, the proposed method SeqGSEA is particularly useful for efficiently translating RNA-Seq data to biological discoveries.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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