Differential exon usage of developmental genes is associated with deregulated epigenetic marks.

Alternative exon usage is known to affect a large portion of genes in mammalian genomes. Importantly, different splice isoforms sometimes possess distinctly different protein functions. Here, we analyzed data from the Human Epigenome Atlas for 11 different human adult tissues and for 8 cultured cells that mimic early developmental stages. We found a significant enrichment of cases where differential usage of exons in various developmental stages of human cells and tissues is associated with differential epigenetic modifications in the flanking regions of individual exons. Many of the genes that were differentially regulated at the exon level and showed deregulated histone marks at the respective exon flanks are functionally associated with development and metabolism.

Drug Discovery of Plausible Lead Natural Compounds That Target the Insulin Signaling Pathway: Bioinformatics Approaches.

The growing smooth talk in the field of natural compounds is due to the ancient and current interest in herbal medicine and their potentially positive effects on health. Dozens of antidiabetic natural compounds were reported and tested in vivo, in silico, and in vitro. The role of these natural compounds, their actions on the insulin signaling pathway, and the stimulation of the glucose transporter-4 (GLUT4) insulin-responsive translocation to the plasma membrane (PM) are all crucial in the treatment of diabetes and insulin resistance. In this review, we collected and summarized a group of available in vivo and in vitro studies which targeted isolated phytochemicals with possible antidiabetic activity. Moreover, the in silico docking of natural compounds with some of the insulin signaling cascade key proteins is also summarized based on the current literature. In this review, hundreds of recent studies on pure natural compounds that alleviate type II diabetes mellitus (type II DM) were revised. We focused on natural compounds that could potentially regulate blood glucose and stimulate GLUT4 translocation through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. On attempt to point out potential new natural antidiabetic compounds, this review also focuses on natural ingredients that were shown to interact with proteins in the insulin signaling pathway in silico, regardless of their in vitro/in vivo antidiabetic activity. We invite interested researchers to test these compounds as potential novel type II DM drugs and explore their therapeutic mechanisms.

In Vitro and In Silico Evaluation for the Inhibitory Action of O. basilicum Methanol Extract on α-Glucosidase and α-Amylase.

Diabetes mellitus is a metabolic disease that predominates, nowadays. It causes hyperglycemia and consequently major health complications. Type II diabetes is the most common form and is a result of insulin resistance in the target tissues. To treat this disease, several mechanisms have been proposed. The most direct route is via inhibiting the intestinal enzymes, e.g., α-glucosidase and α-amylase, responsible for intestinal polysaccharide digestion that therefore would reduce the absorption of monosugars through the intestinal walls. In this study, we shed the light on this route by testing the inhibitory effect of Ocimum basilicum extract on the enzymes α-glucosidase and α-amylase in vitro and in silico. Experimental procedures were performed to test the effect of the O. basilicum methanol extract from aerial parts followed by the in silico docking. 500 µg/mL of the extract led to 70.2% ± 8.6 and 25.4% ± 3.3 inhibition on α-glucosidase and α-amylase activity, respectively. Similarly, the effect of caffeic acid, a major extract ingredient, was also tested, and it caused 42.7% ± 3.0 and 47.1% ± 4.0 inhibition for α-amylase and α-glucosidase, respectively. Docking experiments were performed to predict the phytochemicals responsible for this robust inhibitory activity in the O. basilicum extracts. Several compounds have shown variable levels of inhibition, e.g., caffeic acid, pyroglutamic acid, and uvasol. The results indicated that O. basilicum can be a potent antidiabetic drug.

DNA methylation and the core pluripotency network.

From the onset of fertilization, the genome undergoes cell division and differentiation. All of these developmental transitions and differentiation processes include cell-specific signatures and gradual changes of the epigenome. Understanding what keeps stem cells in the pluripotent state and what leads to differentiation are fascinating and biomedically highly important issues. Numerous studies have identified genes, proteins, microRNAs and small molecules that exert essential effects. Notably, there exists a core pluripotency network that consists of several transcription factors and accessory proteins. Three eminent transcription factors, OCT4, SOX2 and NANOG, serve as hubs in this core pluripotency network. They bind to the enhancer regions of their target genes and modulate, among others, the expression levels of genes that are associated with Gene Ontology terms related to differentiation and self-renewal. Also, much has been learned about the epigenetic rewiring processes during these changes of cell fate. For example, DNA methylation dynamics is pivotal during embryonic development. The main goal of this review is to highlight an intricate interplay of (a) DNA methyltransferases controlling the expression levels of core pluripotency factors by modulation of the DNA methylation levels in their enhancer regions, and of (b) the core pluripotency factors controlling the transcriptional regulation of DNA methyltransferases. We discuss these processes both at the global level and in atomistic detail based on information from structural studies and from computer simulations.

Metabolic and Epigenetic Action Mechanisms of Antidiabetic Medicinal Plants.

Diabetes is a predominant metabolic disease nowadays due to the off-beam lifestyle of diet and reduced physical activity. Complications of the illness include the gene-environment interactions and the downstream genetic and epigenetic consequences, e.g., cardiovascular diseases, tumor progression, retinopathy, nephropathy, neuropathy, polydipsia, polyphagia, polyuria, and weight loss. This review sheds the light on the mechanistic insights of antidiabetic medicinal plants in targeting key organs and tissues involved in regulating blood glucose homeostasis including the pancreas, liver, muscles, adipose tissues, and glucose absorption in the intestine. Diabetes is also involved in modulating major epigenetic pathways such as DNA methylation and histone modification. In this respect, we will discuss the phytochemicals as current and future epigenetic drugs in the treatment of diabetes. In addition, several proteins are common targets for the treatment of diabetes. Some phytochemicals are expected to directly interact with these targets. We lastly uncover modeling studies that predict such plausible interactions. In conclusion, this review article presents the mechanistic insight of phytochemicals in the treatment of diabetes by combining both the cellular systems biology and molecular modeling.

GOTrapper: a tool to navigate through branches of gene ontology hierarchy.

BACKGROUND: Gene Ontology (GO) is a useful resource of controlled vocabulary that provides information about annotated genes. Based on such resource, finding the biological function is useful for biologists to come up with different hypotheses and help further investigations of an experiment. The biological function for desired genes and gene associations is picked up from a randomly chosen list or through the analysis of differential gene expression. Many tools have been developed to utilize GO knowledge and cluster genes according to relevant biological functions. The retrieved GO terms include both specific and non-specific terms, which is not user-friendly in terms of data analysis. Thus one approach is still missing, which allows navigating through different levels of GO hierarchy manually. RESULT: We developed a tool, GOTrapper, which allows moving up or down to the very bottom of the GO hierarchy. This is performed manually by the user, based on an assigned threshold. This tool grabs the shared terms by the desired set of input genes of Homo sapiens. Here, two inputs are possible. "Within" is to find associated terms within one gene list, and "Between" is to find associated terms between two lists. The tool also provides the option to return the terms with the pre-selected evidence codes. CONCLUSION: GOTrapper is a user-friendly Java tool that helps the user move up and down the ontology tree, which leads to new hypotheses and devising new association of the input genes. It also allows returning terms of associated genes based on selected evidence codes. This tool can be accessed and is freely available at https://github.com/BioGeneTools/GOTrapper .

Methylation-targeted specificity of the DNA binding proteins R.DpnI and MeCP2 studied by molecular dynamics simulations.

DNA methylation plays a major role in organismal development and the regulation of gene expression. Methylation of cytosine bases and the cellular roles of methylated cytosine in eukaryotes are well established, as well as methylation of adenine bases in bacterial genomes. Still lacking, however, is a general mechanistic understanding, in structural and thermodynamic terms, of how proteins recognize methylated DNA. Toward this aim, we present the results of molecular dynamics simulations, alchemical free energy perturbation, and MM-PBSA calculations to explain the specificity of the R.DpnI enzyme from Streptococcus pneumonia in binding to adenine-methylated DNA with both its catalytic and winged-helix domains. We found that adenine-methylated DNA binds more favorably to the catalytic subunit of R.DpnI (-4 kcal mol-1) and to the winged-helix domain (-1.6 kcal mol-1) than non-methylated DNA. In particular, N6-adenine methylation is found to enthalpically stabilize binding to R.DpnI. In contrast, C5-cytosine methylation entropically favors complexation by the MBD domain of the human MeCP2 protein with almost no contribution of the binding enthalpy.

Hydration properties of natural and synthetic DNA sequences with methylated adenine or cytosine bases in the R.DpnI target and BDNF promoter studied by molecular dynamics simulations.

Adenine and cytosine methylation are two important epigenetic modifications of DNA sequences at the levels of the genome and transcriptome. To characterize the differential roles of methylating adenine or cytosine with respect to their hydration properties, we performed conventional MD simulations and free energy perturbation calculations for two particular DNA sequences, namely the brain-derived neurotrophic factor (BDNF) promoter and the R.DpnI-bound DNA that are known to undergo methylation of C5-methyl cytosine and N6-methyl adenine, respectively. We found that a single methylated cytosine has a clearly favorable hydration free energy over cytosine since the attached methyl group has a slightly polar character. In contrast, capping the strongly polar N6 of adenine with a methyl group gives a slightly unfavorable contribution to its free energy of solvation. Performing the same demethylation in the context of a DNA double-strand gave quite similar results for the more solvent-accessible cytosine but much more unfavorable results for the rather buried adenine. Interestingly, the same demethylation reactions are far more unfavorable when performed in the context of the opposite (BDNF or R.DpnI target) sequence. This suggests a natural preference for methylation in a specific sequence context. In addition, free energy calculations for demethylating adenine or cytosine in the context of B-DNA vs. Z-DNA suggest that the conformational B-Z transition of DNA transition is rather a property of cytosine methylated sequences but is not preferable for the adenine-methylated sequences investigated here.

Computerized modeling techniques predict the 3D structure of H4R: facts and fiction.

The functional characterization of proteins presents a daily challenge r biochemical, medical and computational sciences, especially when the structures are undetermined empirically, as in the case of the Histamine H4 Receptor (H4R). H4R is a member of the GPCR superfamily that plays a vital role in immune and inflammatory responses. To date, the concept of GPCRs modeling is highlighted in textbooks and pharmaceutical pamphlets, and this group of proteins has been the subject of almost 3500 publications in the scientific literature. The dynamic nature of determining the GPCRs structure was elucidated through elegant and creative modeling methodologies, implemented by many groups around the world. H4R which belongs to the GPCR family was cloned in 2000; understandably, its biological activity was reported only 65 times in pubmed. Here we attempt to cover the fundamental concepts of H4R structure modeling and its implementation in drug discovery, especially those that have been experimentally tested and to highlight some ideas that are currently being discussed on the dynamic nature of H4R and GPCRs computerized techniques for 3D structure modeling.