The 4D Living Genome

2021 ◽  
Author(s):  
Julianna Arlene Sherman Goelzer
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Genomic Sequence ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Correlation Spectroscopy ◽  
Microscopy Technique ◽  
Temporal Aspects ◽  
Key Factor ◽  
Dynamics Simulations

Over the last few decades great advances have been made in our understanding of gene expression and the human genome. In 2003 the human genome was sequenced for the first time, allowing us to discover its true importance in human health. While sequencing the human genome was a great advance, it ultimately created more questions than it answered. It is known that the genomic sequence is extremely important in genome regulation, however recent studies have shown that the 4D (spatiotemporal) organization and dynamics of the living genome plays an equally critical role in regulation of gene expression. A key factor in the spatiotemporal genome is the temporal and spatial coordination of transcription factors required for gene expression. We focus on addressing both the spatial and temporal aspects of the genome through a cutting-edge microscopy technique known as 3D Orbital Tracking Fluorescence Correlation Spectroscopy (3DOT-FCCS) in conjunction with Molecular Dynamics simulations. The synergistic use of these techniques will provide a clearer picture of the rules that govern the human genome.

scholarly journals Exploring different sequence representations and classification methods for the prediction of nucleosome positioning

2018 ◽  
Author(s):  
Nikos Kostagiolas ◽  
Nikiforos Pittaras ◽  
Christoforos Nikolaou ◽  
George Giannakopoulos
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Large Scale ◽  
Genomic Sequence ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Nucleosome Positioning ◽  
Regulatory Elements ◽  
Machine Learning Algorithms ◽  
N Gram

Nucleosomes form the first level of DNA compaction and thus bear a critical role in the overall genome organization. At the same time, they modulate chromatin accessibility and, through a dynamic equilibrium with other DNA-binding proteins, may shape gene expression. A number of large-scale nucleosome positioning maps, obtained for various genomes, has compelled the importance of nucleosomes in the regulation of gene expression and has shown constraints in the relative positions of nucleosomes to be much stronger around regulatory elements (i.e. promoters, splice junctions and enhancers). At the same time, the great majority of nucleosome positions appears to be rather flexible. Various computational methods have in the past been used in order to capture the sequence determinants of nucleosome positioning but, as the extent to which DNA sequence preferences may guide nucleosome occupancy largely varies, this has proved to be rather difficult. In order to focus on highly specific sequence attributes, in this work we have analyzed two well-defined sets of nucleosome-occupied sites (NOS) and nucleosome-free-regions (NFR) from the genome of S. cerevisiae, with the use of textual representations. We employed 3 different genomic sequence representations (Hidden Markov Models, Bag-of-Words and N-gram Graphs) combined with a number of machine learning algorithms on the task of classifying genomic sequences as nucleosome-free (NFR) or nucleosome-occupied NOS (to be further amended based on updated results). We found that different approaches that involve the usage of different representations or algorithms can be more or less effective at predicting nucleosome positioning based on the textual data of the underlying genomic sequence. More interestingly, we show that N-gram Graphs, a sequence representation that takes into account both k-mer occurrences and relative positioning at various lengths scales is outperforming other methodologies and may thus be a choice of preference for the analysis of DNA sequences with subtle constraints.

Chromatin-Modifying Enzymes in T Cell Development

2020 ◽  
Vol 38 (1) ◽  
pp. 397-419
Author(s):  
Michael J. Shapiro ◽  
Virginia Smith Shapiro
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Biological Effects ◽  
Critical Role ◽  
T Cell Development ◽  
Regulation Of Gene Expression ◽  
Chromatin Accessibility ◽  
Cell Development ◽  
Specific Gene ◽  
Dynamic Regulation

T cell development involves stepwise progression through defined stages that give rise to multiple T cell subtypes, and this is accompanied by the establishment of stage-specific gene expression. Changes in chromatin accessibility and chromatin modifications accompany changes in gene expression during T cell development. Chromatin-modifying enzymes that add or reverse covalent modifications to DNA and histones have a critical role in the dynamic regulation of gene expression throughout T cell development. As each chromatin-modifying enzyme has multiple family members that are typically all coexpressed during T cell development, their function is sometimes revealed only when two related enzymes are concurrently deleted. This work has also revealed that the biological effects of these enzymes often involve regulation of a limited set of targets. The growing diversity in the types and sites of modification, as well as the potential for a single enzyme to catalyze multiple modifications, is also highlighted.

scholarly journals Structure-Function Analysis of VapB4 Antitoxin Identifies Critical Features of a Minimal VapC4 Toxin-Binding Module

2015 ◽  
Vol 197 (7) ◽  
pp. 1197-1207 ◽  
Author(s):  
Guangze Jin ◽  
Martin S. Pavelka ◽  
J. Scott Butler
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Function Analysis ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Binding Domain ◽  
Type Ii ◽  
Toxin Binding ◽  
Dna Binding Specificity ◽  
Amino Acid Side Chains

ABSTRACTBacterial toxin-antitoxin systems play a critical role in the regulation of gene expression, leading to developmental changes, reversible dormancy, and cell death. Type II toxin-antitoxin pairs, composed of protein toxins and antitoxins, exist in nearly all bacteria and are classified into six groups on the basis of the structure of the toxins. The VapBC group comprises the most common type II system and, like other toxin-antitoxin systems, functions to elicit dormancy by inhibiting protein synthesis. Activation of toxin function requires protease degradation of the VapB antitoxin, which frees the VapC toxin from the VapBC complex, allowing it to hydrolyze the RNAs required for translation. Generally, type II antitoxins bind with high specificity to their cognate toxins via a toxin-binding domain and endow the complex with DNA-binding specificity via a DNA-binding domain. Despite the ubiquity of VapBC systems and their critical role in the regulation of gene expression, few functional studies have addressed the details of VapB-VapC interactions. Here we report on the results of experiments designed to identify molecular determinants of the specificity of theMycobacterium tuberculosisVapB4 antitoxin for its cognate VapC4 toxin. The results identify the minimal domain of VapB4 required for this interaction as well as the amino acid side chains required for binding to VapC4. These findings have important implications for the evolution of VapBC toxin-antitoxin systems and their potential as targets of small-molecule protein-protein interaction inhibitors.IMPORTANCEVapBC toxin-antitoxin pairs are the most widespread type II toxin-antitoxin systems in bacteria, where they are thought to play key roles in stress-induced dormancy and the formation of persisters. The VapB antitoxins are critical to these processes because they inhibit the activity of the toxins and provide the DNA-binding specificity that controls the synthesis of both proteins. Despite the importance of VapB antitoxins and the existence of several VapBC crystal structures, little is known about their functional featuresin vivo. Here we report the findings of the first comprehensive structure-function analysis of a VapB toxin. The results identify the minimal toxin-binding domain, its modular antitoxin function, and the specific amino acid side chains required for its activity.

Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 25-25
Author(s):  
Yuanyuan Shen ◽  
Justin Hummel ◽  
Isabel Cristina Trindade ◽  
Christos Papageorgiou ◽  
Chi-Ren Shyu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Epigenetic Modification ◽  
Pearson Correlation ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
The Cancer Genome Atlas ◽  
Highly Correlated

25 Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p < 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r > |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.

scholarly journals Differential Expression of MicroRNAs between Eutopic and Ectopic Endometrium in Ovarian Endometriosis

2010 ◽  
Vol 2010 ◽  
pp. 1-29 ◽  
Author(s):  
Nicoletta Filigheddu ◽  
Ilaria Gregnanin ◽  
Paolo E. Porporato ◽  
Daniela Surico ◽  
Beatrice Perego ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Posttranscriptional Regulation ◽  
Noncoding Rna ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Differentially Expressed ◽  
Ovarian Endometriosis ◽  
Eutopic Endometrium ◽  
Ectopic Endometrium

Endometriosis, defined as the presence of endometrial tissue outside the uterus, is a common gynecological disease with poorly understood pathogenesis. MicroRNAs are members of a class of small noncoding RNA molecules that have a critical role in posttranscriptional regulation of gene expression by repression of target mRNAs translation. We assessed differentially expressed microRNAs in ectopic endometrium compared with eutopic endometrium in 3 patients through microarray analysis. We identified 50 microRNAs differentially expressed and the differential expression of five microRNAs was validated by real-time RT-PCR in other 13 patients. We identifiedin silicotheir predicted targets, several of which match the genes that have been identified to be differentially expressed in ectopicversuseutopic endometrium in studies of gene expression. A functional analysis of the predicted targets indicates that several of these are involved in molecular pathways implicated in endometriosis, thus strengthening the hypothesis of the role of microRNAs in this pathology.

scholarly journals Domain-wide regulation of gene expression in the human genome

2007 ◽  
Vol 17 (9) ◽  
pp. 1286-1295 ◽  
Author(s):  
H. J. Gierman ◽  
M. H.G. Indemans ◽  
J. Koster ◽  
S. Goetze ◽  
J. Seppen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Regulation Of Gene Expression

scholarly journals Identification of a transcriptional signature found in multiple models of ASD and related disorders

2022 ◽  
Author(s):  
Samuel Thudium ◽  
Katherine C Palozola ◽  
Eloise L'Her ◽  
Erica Korb
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Neurodevelopmental Disorders ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Autism Spectrum ◽  
Cellular Mechanisms ◽  
Dynamic Regulation ◽  
Transcriptional Signature ◽  
Chromatin Modifiers

Epigenetic regulation plays a critical role in many neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). In particular, many such disorders are the result of mutations in genes that encode chromatin modifying proteins. However, while these disorders share many features, it is unclear whether they also share gene expression disruptions resulting from the aberrant regulation of chromatin. We examined 5 chromatin modifiers that are all linked to ASD despite their different roles in regulating chromatin. Specifically, we depleted Ash1L, Chd8, Crebbp, Ehmt1, and Nsd1 in parallel in a highly controlled neuronal culture system. We then identified sets of shared genes, or transcriptional signatures, that are differentially expressed following loss of multiple ASD-linked chromatin modifiers. We examined the functions of genes within the transcriptional signatures and found an enrichment in many neurotransmitter transport genes and activity-dependent genes. In addition, these genes are enriched for specific chromatin features such as bivalent domains that allow for highly dynamic regulation of gene expression. The downregulated transcriptional signature is also observed within multiple mouse models of neurodevelopmental disorders that result in ASD, but not those only associated with intellectual disability. Finally, the downregulated transcriptional signature can distinguish between neurons generated from iPSCs derived from healthy donors and idiopathic ASD patients through RNA-deconvolution, demonstrating that this gene set is relevant to the human disorder. This work identifies a transcriptional signature that is found within many neurodevelopmental syndromes, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in ASD.

scholarly journals Chromatin-associated protein complexes link DNA base J and transcription termination in Leishmania

2020 ◽  
Author(s):  
Bryan C Jensen ◽  
Isabelle Q. Phan ◽  
Jacquelyn R. McDonald ◽  
Aakash Sur ◽  
Mark A. Gillespie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Protein Complexes ◽  
Transcription Termination ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Control Of Gene Expression ◽  
Polycistronic Transcription ◽  
Post Transcriptional Regulation

AbstractUnlike most other eukaryotes, Leishmania and other trypanosomatid protozoa have largely eschewed transcriptional control of gene expression; relying instead on post-transcriptional regulation of mRNAs derived from polycistronic transcription units (PTUs). In these parasites, a novel modified nucleotide base (β-D-glucopyranosyloxymethyluracil) known as J plays a critical role in ensuring that transcription termination occurs only at the end of each PTU, rather than at the polyadenylation sites of individual genes. To further understand the biology of J-associated processes, we used tandem affinity purification (TAP-tagging) and mass spectrometry to reveal proteins that interact with the glucosyltransferase performing the final step in J synthesis. These studies identified four proteins reminiscent of subunits in the PTW/PP1 complex that controls transcription termination in higher eukaryotes. Moreover, bioinformatic analyses identified the DNA-binding subunit of Leishmania PTW/PP1 as a novel J-binding protein (JBP3). Down-regulation of JBP3 expression levels in Leishmania resulted in a substantial increase in transcriptional read-through at the 3’ end of most PTUs. Additional TAP-tagging experiments showed that JBP3 also associates with two other protein complexes. One consists of subunits with domains suggestive of a role in chromatin modification/remodeling; while the other contains subunits with similarity to those found in the PAF1 complex involved in regulation of transcription in other eukaryotes. Thus, trypanosomatids utilize protein complexes similar to those used to control transcription termination in other eukaryotes and JBP3 appears to function as a hub linking these modules to base J, thereby enabling the parasites’ unique reliance on polycistronic transcription and post-transcriptional regulation of gene expression.

scholarly journals  ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

2018 ◽  
Author(s):  
Miguel Hueso ◽  
Josep M Cruzado ◽  
Joan Torras ◽  
Estanis Navarro
Keyword(s):  
Gene Expression ◽  
Human Genome ◽  
Chaos Theory ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Structural Constraints ◽  
Linear Dynamical Systems ◽  
Alu Elements ◽  
Non Linear ◽  
The Impact

Atherosclerosis (ATH) and Coronary Artery Disease (CAD) are chronic inflammatory diseases with an important genetic background which derive from the cumulative effect of multiple common risk alleles, most of them located in genomic non-coding regions. These complex diseases behave as non-linear dynamical systems that show a high dependence on their initial conditions, so that long-term predictions of disease progression are unreliable. One likely possibility is that the non-linear nature of ATH could be dependent on non-linear correlations in the structure of the human genome. In this review we show how Chaos theory analysis highlighted genomic regions that shared specific structural constraints that could have a role in ATH progression. These regions were shown to be enriched in repetitive sequences of the Alu family, genomic parasites which colonized the human genome, which show a particular secondary structure and have been involved in the regulation of gene expression. We also review the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms by which the Alu elements could alter the inflammatory homeostasis. We devise especial attention to their relationship with the lncRNA ANRIL, the strongest risk factor for ATH, their role as miRNA sponges, and their ability to interfere with the regulatory circuitry of the NF-kB response. We aim to characterize ATH as a non-linear dynamic system in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

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