Recognition of interferon-inducible sites, promoters, and enhancers

BACKGROUND: Computational analysis of gene regulatory regions is important for prediction of functions of many uncharacterized genes. With this in mind, search of the target genes for interferon (IFN) induction appears of interest. IFNs are multi-functional cytokines. Their effects are immunomodulatory, antiviral, antibacterial, and antitumor. The interaction of the IFNs with their cell surface receptors produces an activation of several transcription factors. Four regulatory factors, ISGF3, STAT1, IRF1, and NF-κB, are essential for the function of the IFN system. The aim of this work is the development of computational approaches for the recognition of DNA binding sites for these factors and computer programs for the prediction of the IFN-inducible regions. RESULTS: We developed computational approaches to the recognition of the binding sites for ISGF3, STAT1, IRF1, and NF-κB. Analysis of the distribution of these binding sites demonstrated that the regions -500 upstream of the transcription start site in IFN-inducible genes are enriched in putative binding sites for these transcription factors. Based on selected combinations of the sites whose frequencies were significantly higher than in the other functional gene groups, we developed methods for the prediction of the IFN-inducible promoters and enhancers. We analyzed 1004 sequences of the IFN-inducible genes compiled using microarray data analyses and also about 10,000 human gene sequences from the EPD and RefSeq databases; 74 of 1,664 human genes annotated in EPD were significantly IFN-inducible. CONCLUSION: Analyses of several control datasets demonstrated that the developed methods have a high accuracy of prediction of the IFN-inducible genes. Application of these methods to several datasets suggested that the number of the IFN-inducible genes is approximately 1500–2000 in the human genome

Exploring the Genetic Predisposition to Epigenetic Changes in Alzheimer’s Disease

Alzheimer’s disease (AD) is a prevalent type of dementia in elderly populations with a significant genetic component. The accumulating evidence suggests that AD involves a reconfiguration of the epigenetic landscape, including DNA methylation, post-translational modification of histone proteins, and chromatin remodeling. Along with environmental factors, individual specific genetic features play a considerable role in the formation of epigenetic architecture. In this study, we attempt to identify the non-coding regulatory SNPs (rSNPs) able to affect the epigenetic mechanisms in AD. To this end, the multi-omics approach is used. The GEO (Gene Expression Omnibus) available data (GSE153875) for AD patients and controls are integrated to reveal the rSNPs that display allele-specific features in both ChIP-seq profiles of four histone modifications and RNA-seq. Furthermore, we analyze the presence of rSNPs in the promoters of genes reported to be differentially expressed between AD and the normal brain (AD-related genes) and involved in epigenetic regulation according to the EpiFactors database. We also searched for the rSNPs in the promoters of the genes coding for transcription regulators of the identified AD-related genes. These regulators were selected based on the corresponding ChIP-seq peaks (ENCODE) in the promoter regions of these genes. Finally, we formed a panel of rSNPs localized to the promoters of genes that contribute to the epigenetic landscape in AD and, thus, to the genetic predisposition for this disease

Recognition of interferon-inducible sites, promoters, and enhancers

Abstract Background Computational analysis of gene regulatory regions is important for prediction of functions of many uncharacterized genes. With this in mind, search of the target genes for interferon (IFN) induction appears of interest. IFNs are multi-functional cytokines. Their effects are immunomodulatory, antiviral, antibacterial, and antitumor. The interaction of the IFNs with their cell surface receptors produces an activation of several transcription factors. Four regulatory factors, ISGF3, STAT1, IRF1, and NF-κB, are essential for the function of the IFN system. The aim of this work is the development of computational approaches for the recognition of DNA binding sites for these factors and computer programs for the prediction of the IFN-inducible regions. Results We developed computational approaches to the recognition of the binding sites for ISGF3, STAT1, IRF1, and NF-κB. Analysis of the distribution of these binding sites demonstrated that the regions -500 upstream of the transcription start site in IFN-inducible genes are enriched in putative binding sites for these transcription factors. Based on selected combinations of the sites whose frequencies were significantly higher than in the other functional gene groups, we developed methods for the prediction of the IFN-inducible promoters and enhancers. We analyzed 1004 sequences of the IFN-inducible genes compiled using microarray data analyses and also about 10,000 human gene sequences from the EPD and RefSeq databases; 74 of 1,664 human genes annotated in EPD were significantly IFN-inducible. Conclusion Analyses of several control datasets demonstrated that the developed methods have a high accuracy of prediction of the IFN-inducible genes. Application of these methods to several datasets suggested that the number of the IFN-inducible genes is approximately 1500–2000 in the human genome.</p

Geographical Distribution and Diversity of Gut Microbial NADH:Ubiquinone Oxidoreductase Sequence Associated with Alzheimer's Disease

Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer's disease (AD). Tryptophan is a product of Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough

Novel functional variants at the GWAS-implicated loci might confer risk to major depressive disorder, bipolar affective disorder and schizophrenia

Abstract Background A challenge of understanding the mechanisms underlying cognition including neurodevelopmental and neuropsychiatric disorders is mainly given by the potential severity of cognitive disorders for the quality of life and their prevalence. However, the field has been focused predominantly on protein coding variation until recently. Given the importance of tightly controlled gene expression for normal brain function, the goal of the study was to assess the functional variation including non-coding variation in human genome that is likely to play an important role in cognitive functions. To this end, we organized and utilized available genome-wide datasets from genomic, transcriptomic and association studies into a comprehensive data corpus. We focused on genomic regions that are enriched in regulatory activity—overlapping transcriptional factor binding regions and repurpose our data collection especially for identification of the regulatory SNPs (rSNPs) that showed associations both with allele-specific binding and allele-specific expression. We matched these rSNPs to the nearby and distant targeted genes and then selected the variants that could implicate the etiology of cognitive disorders according to Genome-Wide Association Studies (GWAS). Next, we use DeSeq 2.0 package to test the differences in the expression of the certain targeted genes between the controls and the patients that were diagnosed bipolar affective disorder and schizophrenia. Finally, we assess the potential biological role for identified drivers of cognition using DAVID and GeneMANIA. Results As a result, we selected fourteen regulatory SNPs locating within the loci, implicated from GWAS for cognitive disorders with six of the variants unreported previously. Grouping of the targeted genes according to biological functions revealed the involvement of processes such as ‘posttranscriptional regulation of gene expression’, ‘neuron differentiation’, ‘neuron projection development’, ‘regulation of cell cycle process’ and ‘protein catabolic processes’. We identified four rSNP-targeted genes that showed differential expression between patient and control groups depending on brain region: NRAS—in schizophrenia cohort, CDC25B, DDX21 and NUCKS1—in bipolar disorder cohort. Conclusions Overall, our findings are likely to provide the keys for unraveling the mechanisms that underlie cognitive functions including major depressive disorder, bipolar disorder and schizophrenia etiopathogenesis

A Panel of rSNPs Demonstrating Allelic Asymmetry in Both ChIP-seq and RNA-seq Data and the Search for Their Phenotypic Outcomes through Analysis of DEGs

Currently, the detection of the allele asymmetry of gene expression from RNA-seq data or the transcription factor binding from ChIP-seq data is one of the approaches used to identify the functional genetic variants that can affect gene expression (regulatory SNPs or rSNPs). In this study, we searched for rSNPs using the data for human pulmonary arterial endothelial cells (PAECs) available from the Sequence Read Archive (SRA). Allele-asymmetric binding and expression events are analyzed in paired ChIP-seq data for H3K4me3 mark and RNA-seq data obtained for 19 individuals. Two statistical approaches, weighted z-scores and predicted probabilities, were used to improve the efficiency of finding rSNPs. In total, we identified 14,266 rSNPs associated with both allele-specific binding and expression. Among them, 645 rSNPs were associated with GWAS phenotypes; 4746 rSNPs were reported as eQTLs by GTEx, and 11,536 rSNPs were located in 374 candidate transcription factor binding motifs. Additionally, we searched for the rSNPs associated with gene expression using an SRA RNA-seq dataset for 281 clinically annotated human postmortem brain samples and detected eQTLs for 2505 rSNPs. Based on these results, we conducted Gene Ontology (GO), Disease Ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and constructed the protein–protein interaction networks to represent the top-ranked biological processes with a possible contribution to the phenotypic outcome

Brilliant Scientist, Educator and Organizer. The 75-Year Anniversary of Professor, Doctor of Technical Sciences V.S. Biront

В мемориальной статье, посвященной 75-летнему юбилею профессора, доктора технических наук В.С. Биронта (1937-2011), представлены основные направления научной работы выдающегося металловеда Сибири, его яркой педагогической и организаторской деятельности.Memorial article on 75-year anniversary of the Professor, doctor of technical sciences V. S. Biront (1937-2011) presented the main directions of scientific work of outstanding metallographer of Siberia, its shining pedagogical and organisational activities

Brilliant Scientist, Educator and Organizer. The 75-Year Anniversary of Professor, Doctor of Technical Sciences V.S. Biront

В мемориальной статье, посвященной 75-летнему юбилею профессора, доктора технических наук В.С. Биронта (1937-2011), представлены основные направления научной работы выдающегося металловеда Сибири, его яркой педагогической и организаторской деятельности.Memorial article on 75-year anniversary of the Professor, doctor of technical sciences V. S. Biront (1937-2011) presented the main directions of scientific work of outstanding metallographer of Siberia, its shining pedagogical and organisational activities