The use of artificial data to evaluate the performance of aligners and peak callers not only improves its accuracy and reliability, but also makes it possible to reduce the computational time. One of the natural ways to achieve such time reduction is by mapping a single chromosome.

Genomes are organized into high-level three-dimensional structures, and DNA elements separated by long genomic distances can in principle interact functionally. Many transcription factors bind to regulatory DNA elements distant from gene promoters. Although distal binding sites have been shown to regulate transcription by long-range chromatin interactions at a few loci, chromatin interactions and their impact on transcription regulation have not been investigated in a genome-wide manner. Here we describe the development of a new strategy, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) for the de novo detection of global chromatin interactions, with which we have comprehensively mapped the chromatin interaction network bound by oestrogen receptor alpha (ER-alpha) in the human genome. We found that most high-confidence remote ER-alpha-binding sites are anchored at gene promoters through long-range chromatin interactions, suggesting that ER-alpha functions by extensive chromatin looping to bring genes together for coordinated transcriptional regulation. We propose that chromatin interactions constitute a primary mechanism for regulating transcription in mammalian genomes.

The development of essential hypertension is associated with a wide range of mechanisms. The brain stem neurons are essential for the homeostatic regulation of arterial pressure as they control baroreflex and sympathetic nerve activity. The ISIAH (Inherited Stress Induced Arterial Hypertension) rats reproduce the human stress-sensitive hypertensive disease with predominant activation of the neuroendocrine hypothalamic-pituitary-adrenal and sympathetic adrenal axes. RNA-Seq analysis of the brain stems from the hypertensive ISIAH and normotensive control WAG (Wistar Albino Glaxo) rats was performed to identify the differentially expressed genes (DEGs) and the main central mechanisms (biological processes and metabolic pathways) contributing to the hypertensive state in the ISIAH rats.

Cold and drought are two of the most severe threats affecting the growth and productivity of the tea plant, limiting its global spread. Both stresses cause osmotic changes in the cells of the tea plant by decreasing their water potential. To develop cultivars that are tolerant to both stresses, it is essential to understand the genetic responses of tea plant to these two stresses, particularly in terms of the genes involved. In this study, we combined literature data with interspecific transcriptomic analyses (using Arabidopsis thaliana and Solanum lycopersicum) to choose genes related to cold tolerance. We identified 45 stress-inducible candidate genes associated with cold and drought responses in tea plants based on a comprehensive homologous detection method. Of these, nine were newly characterized by us, and 36 had previously been reported. The gene network analysis revealed upregulated expression in ICE1-related cluster of bHLH factors, HSP70/BAM5 connected genes (hexokinases, galactinol synthases, SnRK complex, etc.) indicating their possible co-expression. Using qRT-PCR we revealed that 10 genes were significantly upregulated in response to both cold and drought in tea plant: HSP70, GST, SUS1, DHN1, BMY5, bHLH102, GR-RBP3, ICE1, GOLS1, and GOLS3. SnRK1.2, HXK1/2, bHLH7/43/79/93 were specifically upregulated in cold, while RHL41, CAU1, Hydrolase22 were specifically upregulated in drought. Interestingly, the expression of CIP was higher in the recovery stage of both stresses, indicating its potentially important role in plant recovery after stress. In addition, some genes, such as DHN3, bHLH79, PEI54, SnRK1.2, SnRK1.3, and Hydrolase22, were significantly positively correlated between the cold and drought responses. CBF1, GOLS1, HXK2, and HXK3, by contrast, showed significantly negative correlations between the cold and drought responses. Our results provide valuable information and robust candidate genes for future functional analyses intended to improve the stress tolerance of the tea plant and other species.

Genetic regulation is known to contribute to the divergent expression of duplicate genes; however, little is known about how epigenetic modifications regulate the expression of duplicate genes in plants.

Cold and frost are two serious factors limiting the yield of many crops worldwide, including the tea plant (Camellia sinensis (L.) Kuntze). The acclimatization of tea plant from tropical to temperate climate regions resulted in unique germplasm in the North-Western Caucasus with extremely frost-tolerant genotypes.

Applications of Artificial Intelligence in medical informatics solutions risk sharing have social value. At a time of ever-increasing cost for the provision of medicines to citizens, there is a need to restrain the growth of health care costs. The search for computer technologies to stop or slow down the growth of costs acquires a new very important and significant meaning. We discussed the two information technologies in pharmacotherapy and the possibility of combining and sharing them, namely the combination of risk-sharing agreements and Machine Learning, which was made possible by the development of Artificial Intelligence (AI). Neural networks could be used to predict the outcome to reduce the risk factors for treatment. AI-based data processing automation technologies could be also used for risk-sharing agreements automation.

Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs, and Mprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach may be used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with "ribosomopathies."

Higher-order chromosomal organization for transcription regulation is poorly understood in eukaryotes. Using genome-wide Chromatin Interaction Analysis with Paired-End-Tag sequencing (ChIA-PET), we mapped long-range chromatin interactions associated with RNA polymerase II in human cells and uncovered widespread promoter-centered intragenic, extragenic, and intergenic interactions. These interactions further aggregated into higher-order clusters, wherein proximal and distal genes were engaged through promoter-promoter interactions. Most genes with promoter-promoter interactions were active and transcribed cooperatively, and some interacting promoters could influence each other implying combinatorial complexity of transcriptional controls. Comparative analyses of different cell lines showed that cell-specific chromatin interactions could provide structural frameworks for cell-specific transcription, and suggested significant enrichment of enhancer-promoter interactions for cell-specific functions. Furthermore, genetically-identified disease-associated noncoding elements were found to be spatially engaged with corresponding genes through long-range interactions. Overall, our study provides insights into transcription regulation by three-dimensional chromatin interactions for both housekeeping and cell-specific genes in human cells.

Epigenetic modifications are crucial for proper lineage specification and embryo development. To explore the chromatin modification landscapes in human ES cells, we profiled two histone modifications, H3K4me3 and H3K27me3, by ChIP coupled with the paired-end ditags sequencing strategy. H3K4me3 was found to be a prevalent mark and occurred in close proximity to the promoters of two-thirds of total human genes. Among the H3K27me3 loci identified, 56% are associated with promoters and the vast majority of them are comodified by H3K4me3. By deep-transcript digital counting, 80% of H3K4me3 and 36% of comodified promoters were found to be transcribed. Remarkably, we observed that different combinations of histone methylations are associated with genes from distinct functional categories. These global histone methylation maps provide an epigenetic framework that enables the discovery of novel transcriptional networks and delineation of different genetic compartments of the pluripotent cell genome.

No abstract available

The development of high-throughput genomic sequencing coupled with chromatin immunoprecipitation technologies allows studying the binding sites of the protein transcription factors (TF) in the genome scale. The growth of data volume on the experimentally determined binding sites raises qualitatively new problems for the analysis of gene expression regulation, prediction of transcription factors target genes, and regulatory gene networks reconstruction. Genome regulation remains an insufficiently studied though plants have complex molecular regulatory mechanisms of gene expression and response to environmental stresses. It is important to develop new software tools for the analysis of the TF binding sites location and their clustering in the plant genomes, visualization, and the following statistical estimates. This study presents application of the analysis of multiple TF binding profiles in three evolutionarily distant model plant organisms. The construction and analysis of non-random ChIP-seq binding clusters of the different TFs in mammalian embryonic stem cells were discussed earlier using similar bioinformatics approaches. Such clusters of TF binding sites may indicate the gene regulatory regions, enhancers and gene transcription regulatory hubs. It can be used for analysis of the gene promoters as well as a background for transcription networks reconstruction. We discuss the statistical estimates of the TF binding sites clusters in the model plant genomes. The distributions of the number of different TFs per binding cluster follow same power law distribution for all the genomes studied. The binding clusters in Arabidopsis thaliana genome were discussed here in detail.

Crop plant breeding involves selecting and developing new plant varieties with desirable traits such as increased yield, improved disease resistance, and enhanced nutritional value. With the development of high-throughput technologies, such as genomics, transcriptomics, and metabolomics, crop breeding has entered a new era. However, to effectively use these technologies, integration of multi-omics data from different databases is required. Integration of omics data provides a comprehensive understanding of the biological processes underlying plant traits and their interactions. This review highlights the importance of integrating omics databases in crop plant breeding, discusses available omics data and databases, describes integration challenges, and highlights recent developments and potential benefits. Taken together, the integration of omics databases is a critical step towards enhancing crop plant breeding and improving global food security.

A major question in transcription factor (TF) biology is why a TF binds to only a small fraction of motif eligible binding sites in the genome. Using the estrogen receptor-α as a model system, we sought to explicitly define parameters that determine TF-binding site selection. By examining 12 genetic and epigenetic parameters, we find that an energetically favorable estrogen response element (ERE) motif sequence, co-occupancy by the TF FOXA1, the presence of the H3K4me1 mark and an open chromatin configuration in the pre-ligand state provide specificity for ER binding. These factors can model estrogen-induced ER binding with high accuracy (ROC-AUC=0.95 and 0.88 using different genomic backgrounds). Moreover, when assessed in another estrogen-responsive cell line, this model was highly predictive for ERα binding (ROC-AUC=0.86). Variance in binding site selection between MCF-7 and T47D resides in sites with suboptimal ERE motifs, but modulated by the chromatin configuration. These results suggest a definable interplay between sequence motifs and local chromatin in selecting TF binding.

Induced pluripotent stem (iPS) cells can be obtained by the introduction of defined factors into somatic cells. The combination of Oct4 (also known as Pou5f1), Sox2 and Klf4 (which we term OSK) constitutes the minimal requirement for generating iPS cells from mouse embryonic fibroblasts. These cells are thought to resemble embryonic stem cells (ESCs) on the basis of global gene expression analyses; however, few studies have tested the ability and efficiency of iPS cells to contribute to chimaerism, colonization of germ tissues, and most importantly, germ-line transmission and live birth from iPS cells produced by tetraploid complementation. Using genomic analyses of ESC genes that have roles in pluripotency and fusion-mediated somatic cell reprogramming, here we show that the transcription factor Tbx3 significantly improves the quality of iPS cells. iPS cells generated with OSK and Tbx3 (OSKT) are superior in both germ-cell contribution to the gonads and germ-line transmission frequency. However, global gene expression profiling could not distinguish between OSK and OSKT iPS cells. Genome-wide chromatin immunoprecipitation sequencing analysis of Tbx3-binding sites in ESCs suggests that Tbx3 regulates pluripotency-associated and reprogramming factors, in addition to sharing many common downstream regulatory targets with Oct4, Sox2, Nanog and Smad1. This study underscores the intrinsic qualitative differences between iPS cells generated by different methods, and highlights the need to rigorously characterize iPS cells beyond in vitro studies.

The knowledge about specific mechanisms generating TP53 dysfunction in diffuse large B-cell lymphoma is limited. The aim of the current study was to comprehensively explore TP53 gene variability resulting from somatic mutations, promoter methylation, and allelic imbalance in tumorous tissue of diffuse large B-cell lymphoma (DLBCL).

The large scale genome wide association studies (GWAS) have identified approximately 80 single nucleotide polymorphisms (SNPs) conferring susceptibility to type 2 diabetes (T2D). However, most of these loci have not been replicated in diverse populations and much genetic heterogeneity has been observed across ethnic groups. We tested 28 SNPs previously found to be associated with T2D by GWAS in a Mongolian sample of Northern China (497 diagnosed with T2D and 469 controls) for association with T2D and diabetes related quantitative traits. We replicated T2D association of 11 SNPs, namely, rs7578326 (IRS1), rs1531343 (HMGA2), rs8042680 (PRC1), rs7578597 (THADA), rs1333051 (CDKN2), rs6723108 (TMEM163), rs163182 and rs2237897 (KCNQ1), rs1387153 (MTNR1B), rs243021 (BCL11A), and rs10229583 (PAX4) in our sample. Further, we showed that risk allele of the strongest T2D associated SNP in our sample, rs757832 (IRS1), is associated with increased level of TG. We observed substantial difference of T2D risk allele frequency between the Mongolian sample and the 1000G Caucasian sample for a few SNPs, including rs6723108 (TMEM163) whose risk allele reaches near fixation in the Mongolian sample. Further study of genetic architecture of these variants in susceptibility of T2D is needed to understand the role of these variants in heterogeneous populations.

Boron neutron capture therapy (BNCT) is based on the ability of the boron-10 (10B) isotope to capture epithermal neutrons, as a result of which the isotope becomes unstable and decays into kinetically active elements that destroy cells where the nuclear reaction has occurred. The boron-carrying compounds-L-para-boronophenylalanine (BPA) and sodium mercaptoundecahydro-closo-dodecaborate (BSH)-have low toxicity and, today, are the only representatives of such compounds approved for clinical trials. For the effectiveness and safety of BNCT, a low boron content in normal tissues and substantially higher content in tumor tissue are required. This study evaluated the boron concentration in intracranial grafts of human glioma U87MG cells and normal tissues of the brain and other organs of mice at 1, 2.5 and 5 h after administration of the boron-carrying compounds. A detailed statistical analysis of the boron biodistribution dynamics was performed to find a 'window of opportunity' for BNCT. The data demonstrate variations in boron accumulation in different tissues depending on the compound used, as well as significant inter-animal variation. The protocol of administration of BPA and BSH compounds used did not allow achieving the parameters necessary for the successful course of BNCT in a glioma orthotopic xenograft mouse model.

Cis-antisense gene pairs (CASGPs) can transcribe mRNAs from an opposite strand of a given locus. To classify and understand diverse CASGP phenomena in the human we compiled a genome-wide catalog of CASGPs and integrated these sequences with microarray, SAGE and miRNA data. Using the concept of overlapping regions and clustering of SA transcripts by chromosome coordinates, we identified up to 9000 overlapping antisense loci. Four thousand three hundred and seventy-four of these CASGPs form 1759 complex gene architectures. We found that approximately 35% (6347/18160) of RefSeq genes are overlapped with the antisense transcripts. About 30% of Affymetrix U133 microarray initial sequences map transcripts of approximately 35% CASGPs and reveal mostly concordant expression in CASGPs. We found strong significant overrepresentation of human miRNA genes in loci of CASGPs. We developed a data-driven model of cross-talk between co-expressed CASGPs and DICER1-mediated miRNA pathway in normal spermatogenesis and in severe teratozoospermia. Specifically, we revealed complex SA structural-functional gene module composing the protein-coding genes, WDR6, DALRD3, NDUFAF3 and ncRNA precursors, mir-425 and mir-191, which could provide downregulation of ncRNA pathway via direct targeting DICER1 and basonuclin 2 transcripts by mir-425 and mir-191 in normal spermatogenesis, but this mechanism is switched off in severe teratozoospermia. The database is available from http://globalisland.bii.a-star.edu.sg/ approximately jiangtao/sas/index3.php?link =about.

Eukaryotic genomes encode thousands of non-coding RNAs (ncRNAs), which play crucial roles in transcriptional and post-transcriptional regulation of gene expression. Accumulating evidence indicates that ncRNAs, especially microRNAs (miRNAs) and long ncRNAs (lncRNAs), have emerged as key regulatory molecules in plant stress responses. In this review, we have summarized the current progress on the understanding of plant miRNA and lncRNA identification, characteristics, bioinformatics tools, and resources, and provided examples of mechanisms of miRNA- and lncRNA-mediated plant stress tolerance.