scholarly journals Integration and Visualization of Regulatory Elements and Variations of the EPAS1 Gene in Human

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1793
Author(s):  
Aleša Kristan ◽  
Nataša Debeljak ◽  
Tanja Kunej
Keyword(s):  
Target Genes ◽  
Regulatory Elements ◽  
Future Research ◽  
Protein Abundance ◽  
Interacting Proteins ◽  
Pas Domain ◽  
Expression Stability ◽  
Post Translational Modifications ◽  
Oxygen Homeostasis ◽  
Cancer Types

Endothelial PAS domain-containing protein 1 (EPAS1), also HIF2α, is an alpha subunit of hypoxia-inducible transcription factor (HIF), which mediates cellular and systemic response to hypoxia. EPAS1 has an important role in the transcription of many hypoxia-responsive genes, however, it has been less researched than HIF1α. The aim of this study was to integrate an increasing number of data on EPAS1 into a map of diverse OMICs elements. Publications, databases, and bioinformatics tools were examined, including Ensembl, MethPrimer, STRING, miRTarBase, COSMIC, and LOVD. The EPAS1 expression, stability, and activity are tightly regulated on several OMICs levels to maintain complex oxygen homeostasis. In the integrative EPAS1 map we included: 31 promoter-binding proteins, 13 interacting miRNAs and one lncRNA, and 16 post-translational modifications regulating EPAS1 protein abundance. EPAS1 has been associated with various cancer types and other diseases. The development of neuroendocrine tumors and erythrocytosis was shown to be associated with 11 somatic and 20 germline variants. The integrative map also includes 12 EPAS1 target genes and 27 interacting proteins. The study introduced the first integrative map of diverse genomics, transcriptomics, proteomics, regulomics, and interactomics data associated with EPAS1, to enable a better understanding of EPAS1 activity and regulation and support future research.

scholarly journals Identification of key genes and associated pathways in neuroendocrine tumors through bioinformatics analysis and predictions of small drug molecules

2020 ◽  
Author(s):  
Praveenkumar Devarbhavi ◽  
Basavaraj Vastrad ◽  
Anandkumar Tengli ◽  
Chanabasayya Vastrad ◽  
Iranna Kotturshetti
Keyword(s):  
Drug Target ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Elements ◽  
Future Research ◽  
High Morbidity ◽  
Hub Genes ◽  
Go Enrichment ◽  
Significant Difference

AbstractNeuroendocrine tumor (NET) is one of malignant cancer and is identified with high morbidity and mortality rates around the world. With indigent clinical outcomes, potential biomarkers for diagnosis, prognosis and drug target are crucial to explore. The aim of this study is to examine the gene expression module of NET and to identify potential diagnostic and prognostic biomarkers as well as to find out new drug target. The differentially expressed genes (DEGs) identified from GSE65286 dataset was used for pathway enrichment analyses and gene ontology (GO) enrichment analyses and protein - protein interaction (PPI) analysis and module analysis. Moreover, miRNAs and transcription factors (TFs) that regulated the up and down regulated genes were predicted. Furthermore, validation of hub genes was performed. Finally, molecular docking studies were performed. DEGs were identified, including 453 down regulated and 459 up regulated genes. Pathway and GO enrichment analysis revealed that DEGs were enriched in sucrose degradation, creatine biosynthesis, anion transport and modulation of chemical synaptic transmission. Important hub genes and target genes were identified through PPI network, modules, target gene - miRNA network and target gene - TF network. Finally, survival analyses, receiver operating characteristic (ROC) curve and RT-PCR validated the significant difference of ATP1A1, LGALS3, LDHA, SYK, VDR, OBSL1, KRT40, WWOX, NINL and PPP2R2B between metastatic NET and normal controls. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying NET and provide candidate targets for future research.

scholarly journals NEAT-seq: Simultaneous profiling of intra-nuclear proteins, chromatin accessibility, and gene expression in single cells

2021 ◽  
Author(s):  
Amy F Chen ◽  
Benjamin Parks ◽  
Arwa Kathiria ◽  
Benjamin Ober-Reynolds ◽  
Jorg Goronzy ◽  
...  
Keyword(s):  
T Cells ◽  
High Throughput Sequencing ◽  
Target Genes ◽  
Nuclear Protein ◽  
Single Cells ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
T Cell Subsets ◽  
Protein Abundance ◽  
Joint Measurement

Oligonucleotide-conjugated antibodies have allowed for joint measurement of surface protein abundance and the transcriptome in single cells using high-throughput sequencing. Extending these measurements to gene regulatory proteins in the nucleus would provide a powerful means to link changes in abundance of trans-acting TFs to changes in activity of cis-acting elements and expression of target genes. Here, we introduce Nuclear protein Epitope, chromatin Accessibility, and Transcriptome sequencing (NEAT-seq), a technique to simultaneously measure nuclear protein abundance, chromatin accessibility, and the transcriptome in single cells. We apply this technique to profile CD4 memory T cells using a panel of master transcription factors (TFs) that drive distinct helper T cell subsets and regulatory T cells (Tregs) and identify examples of TFs with regulatory activity gated by three distinct mechanisms: transcription, translation, and regulation of chromatin binding. Furthermore, we identify regulatory elements and target genes associated with each TF, which we use to link a non-coding GWAS SNP within a GATA motif to both strong allele-specific chromatin accessibility in cells expressing high levels of GATA3 protein, and a putative target gene.

scholarly journals Nkx2.5-dependent alterations of the embryonic heart DNA methylome identify novel cis-regulatory elements in cardiac development

2017 ◽  
Author(s):  
Bushra Gorsi ◽  
Timothy L. Mosbruger ◽  
Megan Smith ◽  
Jonathon T. Hill ◽  
H. Joseph Yost
Keyword(s):  
Dna Methylation ◽  
Heart Development ◽  
Target Genes ◽  
Cardiac Development ◽  
Regulatory Elements ◽  
Cardiac Morphogenesis ◽  
Post Translational Modifications ◽  
Binding Motifs ◽  
Dna Methylome ◽  
Methylation Patterns

AbstractTranscription factor Nkx2.5 is frequently mutated in congenital heart disease, but the mechanisms by which Nkx2.5 regulates heart development are poorly understood. By generating comprehensive DNA methylome maps from zebrafish embryonic hearts in nxk2.5 mutants and siblings, we discovered that Nkx2.5 regulates DNA methylation patterns during cardiac morphogenesis. We identified hundreds of Nkx-dependent heart-specific Differentially Methylated Regions (nhDMRs). A majority of the nhDMRs were hypomethylated in nkx2.5−/- hearts, correlating with changes in the mutant transcriptome, suggesting Nkx2.5 functions largely as a repressor. Distinct Nkx DNA-binding motifs were significantly enriched in subclasses of nhDMRs. Furthermore, nhDMRs were significantly associated with histone H3K4me1 and H3K27ac post-translational modifications, suggesting Nkx2.5 regulates gene expression by differential methylation of cis-regulatory elements. Using transgenics, we validated several nhDMRs with enhancer activities in the heart. We propose a novel role of Nkx2.5 mediated DNA methylation is integral in activating and repressing Nkx2.5 target genes during heart development.

scholarly journals Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yihui Zhou ◽  
Xiaomeng Gao ◽  
Meng Yuan ◽  
Bo Yang ◽  
Qiaojun He ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Cancer Treatment ◽  
Half Life ◽  
Target Genes ◽  
Interacting Proteins ◽  
Hematologic Neoplasms ◽  
Invasion And Metastasis ◽  
Post Translational Modifications ◽  
The Stability ◽  
Low Expression

MYC, as a well-known oncogene, plays essential roles in promoting tumor occurrence, development, invasion and metastasis in many kinds of solid tumors and hematologic neoplasms. In tumors, the low expression and the short half-life of Myc are reversed, cause tumorigenesis. And proteins that directly interact with different Myc domains have exerted a significant impact in the process of Myc-driven carcinogenesis. Apart from affecting the transcription of Myc target genes, Myc interaction proteins also regulate the stability of Myc through acetylation, methylation, phosphorylation and other post-translational modifications, as well as competitive combination with Myc. In this review, we summarize a series of Myc interacting proteins and recent advances in the related inhibitors, hoping that can provide new opportunities for Myc-driven cancer treatment.

Dicarbonyl derived post-translational modifications: chemistry bridging biology and aging-related disease

2020 ◽  
Vol 64 (1) ◽  
pp. 97-110
Author(s):  
Christian Sibbersen ◽  
Mogens Johannsen
Keyword(s):  
Mass Spectrometry ◽  
Future Research ◽  
Amino Acid Residues ◽  
Post Translational Modification ◽  
Dicarbonyl Compounds ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Reactive Protein ◽  
Glycation End Products ◽  
Direct Mass Spectrometry

Abstract In living systems, nucleophilic amino acid residues are prone to non-enzymatic post-translational modification by electrophiles. α-Dicarbonyl compounds are a special type of electrophiles that can react irreversibly with lysine, arginine, and cysteine residues via complex mechanisms to form post-translational modifications known as advanced glycation end-products (AGEs). Glyoxal, methylglyoxal, and 3-deoxyglucosone are the major endogenous dicarbonyls, with methylglyoxal being the most well-studied. There are several routes that lead to the formation of dicarbonyl compounds, most originating from glucose and glucose metabolism, such as the non-enzymatic decomposition of glycolytic intermediates and fructosyl amines. Although dicarbonyls are removed continuously mainly via the glyoxalase system, several conditions lead to an increase in dicarbonyl concentration and thereby AGE formation. AGEs have been implicated in diabetes and aging-related diseases, and for this reason the elucidation of their structure as well as protein targets is of great interest. Though the dicarbonyls and reactive protein side chains are of relatively simple nature, the structures of the adducts as well as their mechanism of formation are not that trivial. Furthermore, detection of sites of modification can be demanding and current best practices rely on either direct mass spectrometry or various methods of enrichment based on antibodies or click chemistry followed by mass spectrometry. Future research into the structure of these adducts and protein targets of dicarbonyl compounds may improve the understanding of how the mechanisms of diabetes and aging-related physiological damage occur.

scholarly journals Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 433
Author(s):  
Bijesh George ◽  
P. Mukundan Pillai ◽  
Aswathy Mary Paul ◽  
Revikumar Amjesh ◽  
Kim Leitzel ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Survival Duration ◽  
Cancer Drug ◽  
Targeted Therapeutics ◽  
Cellular Targets ◽  
Human Cancer Cells ◽  
Cancer Types

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

scholarly journals Novel Roles for the Sirtuin Deacylase SIRT5 in Normal Physiology and in Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 741-741
Author(s):  
David Lombard
Keyword(s):  
Mitochondrial Matrix ◽  
Genomic Integrity ◽  
Biological Functions ◽  
Protein Targets ◽  
Post Translational Modifications ◽  
Catalytic Activities ◽  
Cellular Processes ◽  
Specific Cancer ◽  
Cancer Types ◽  
Chromatin Biology

Abstract Sirtuins are NAD+-dependent deacylases that regulate diverse cellular processes such as metabolic homeostasis and genomic integrity. Mammals possess seven sirtuin family members, SIRT1-SIRT7, that display diverse subcellular localization patterns, catalytic activities, protein targets, and biological functions. Three sirtuins, SIRT3, SIRT4, and SIRT5, are primarily located in the mitochondrial matrix. SIRT5 is a very inefficient deacetylase, instead removing negatively charged post-translational modifications (succinyl, glutaryl, and malonyl groups) from lysines of its target proteins, in mitochondria and throughout the cell. SIRT5 plays only modest known roles in normal physiology, with its major functions occurring in the heart under stress conditions. In contrast, in specific cancer types, including melanoma, we have identified a major pro-survival role for SIRT5. We have traced this function of SIRT5 to novel roles for this protein in regulating chromatin biology. New insights into mechanisms of SIRT5 action in cancer, and in normal myocardium, will be discussed.

scholarly journals mHealth Interventions to Address Physical Activity and Sedentary Behavior in Cancer Survivors: A Systematic Review

2021 ◽  
Vol 18 (11) ◽  
pp. 5798
Author(s):  
Selina Khoo ◽  
Najihah Mohbin ◽  
Payam Ansari ◽  
Mahfoodha Al-Kitani ◽  
Andre Matthias Müller
Keyword(s):  
Physical Activity ◽  
Cancer Survivors ◽  
Sedentary Behavior ◽  
Total Activity ◽  
Personal Contact ◽  
Future Research ◽  
Controlled Trials ◽  
Cancer Types ◽  
Study Participants ◽  
Multicomponent Interventions

This review aimed to identify, evaluate, and synthesize the scientific literature on mobile health (mHealth) interventions to promote physical activity (PA) or reduce sedentary behavior (SB) in cancer survivors. We searched six databases from 2000 to 13 April 2020 for controlled and non-controlled trials published in any language. We conducted best evidence syntheses on controlled trials to assess the strength of the evidence. All 31 interventions included in this review measured PA outcomes, with 10 of them also evaluating SB outcomes. Most study participants were adults/older adults with various cancer types. The majority (n = 25) of studies implemented multicomponent interventions, with activity trackers being the most commonly used mHealth technology. There is strong evidence for mHealth interventions, including personal contact components, in increasing moderate-to-vigorous intensity PA among cancer survivors. However, there is inconclusive evidence to support mHealth interventions in increasing total activity and step counts. There is inconclusive evidence on SB potentially due to the limited number of studies. mHealth interventions that include personal contact components are likely more effective in increasing PA than mHealth interventions without such components. Future research should address social factors in mHealth interventions for PA and SB in cancer survivors.

scholarly journals Histone Modifying Enzymes in Gynaecological Cancers

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 816
Author(s):  
Priya Ramarao-Milne ◽  
Olga Kondrashova ◽  
Sinead Barry ◽  
John D. Hooper ◽  
Jason S. Lee ◽  
...  
Keyword(s):  
Genome Instability ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Driver Mutations ◽  
Promoter Regions ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
Cancer Types ◽  
Histone Modifying Enzymes

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.

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