scholarly journals Structure of the human SAGA coactivator complex: The divergent architecture of human SAGA allows modular coordination of transcription activation and co-transcriptional splicing

2021 ◽  
Author(s):  
Dominik A. Herbst ◽  
Meagan N. Esbin ◽  
Robert K. Louder ◽  
Claire Dugast-Darzacq ◽  
Gina M. Dailey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Transcription Activation ◽  
Structural Features ◽  
Functional Modules ◽  
Specific Requirement ◽  
The Core ◽  
Human Complex ◽  
Activator Complex ◽  
Coactivator Complex

AbstractHuman SAGA is an essential co-activator complex that regulates gene expression by interacting with enhancer-bound activators, recruiting transcriptional machinery, and modifying chromatin near promoters. Subunit variations and the metazoan-specific requirement of SAGA in development hinted at unique structural features of the human complex. Our 2.9 Å structure of human SAGA reveals intertwined functional modules flexibly connected to a core that distinctively integrates mammalian paralogs, incorporates U2 splicing subunits, and features a unique interface between the core and the activator-binding TRRAP. Our structure sheds light on unique roles and regulation of human coactivators with implications for transcription and splicing that have relevance in genetic diseases and cancer.

scholarly journals Identification of genes and functional coexpression modules closely related to ulcerative colitis by gene datasets analysis

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8061 ◽  
Author(s):  
Jie Zhu ◽  
Zheng Wang ◽  
Fengzhe Chen ◽  
Changhong Liu
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Tyrosine Kinases ◽  
Gene Expression Signature ◽  
Enrichment Analysis ◽  
Rank Aggregation ◽  
Integrated Analysis ◽  
Pathway Enrichment Analysis ◽  
Functional Modules ◽  
The Core

Background Ulcerative colitis is a type of inflammatory bowel disease posing a great threat to the public health worldwide. Previously, gene expression studies of mucosal colonic biopsies have provided some insight into the pathophysiological mechanisms in ulcerative colitis; however, the exact pathogenesis is unclear. The purpose of this study is to identify the most related genes and pathways of UC by bioinformatics, so as to reveal the core of the pathogenesis. Methods Genome-wide gene expression datasets involving ulcerative colitis patients were collected from gene expression omnibus database. To identify most close genes, an integrated analysis of gene expression signature was performed by employing robust rank aggregation method. We used weighted gene co-expression network analysis to explore the functional modules involved in ulcerative colitis pathogenesis. Besides, biological process and pathways analysis of co-expression modules were figured out by gene ontology enrichment analysis using Metascape. Results A total of 328 ulcerative colitis patients and 138 healthy controls were from 14 datasets. The 150 most significant differentially expressed genes are likely to include causative genes of disease, and further studies are needed to demonstrate this. Seven main functional modules were identified, which pathway enrichment analysis indicated were associated with many biological processes. Pathways such as ‘extracellular matrix, immune inflammatory response, cell cycle, material metabolism’ are consistent with the core mechanism of ulcerative colitis. However, ‘defense response to virus’ and ‘herpes simplex infection’ suggest that viral infection is one of the aetiological agents. Besides, ‘Signaling by Receptor Tyrosine Kinases’ and ‘pathway in cancer’ provide new clues for the study of the risk and process of ulcerative colitis cancerization.

Post-Transcriptional Regulation of Cardiac Sarcomere Protein Titin Through 3’ Untranslated Regions

2013 ◽  
Vol 9 ◽  
Author(s):  
Tara A Shrout
Keyword(s):  
Gene Expression ◽  
Transcriptional Control ◽  
Striated Muscle ◽  
Binding Capacity ◽  
Structural Features ◽  
Neonatal Rat ◽  
Regulatory Control ◽  
Untranslated Regions ◽  
Luciferase Reporter ◽  
Regulatory Effects

Titin is the largest known protein in the human body, and forms the backbone of all striated muscle sarcomeres. The elastic nature of titin is an important component of muscle compliance and functionality. A significant amount of energy is expended to synthesize titin, thus we postulate that titin gene expression is under strict regulatory control in order to conserve cellular resources. In general, gene expression is mediated in part by post-transcriptional control elements located within the 5’ and 3’ untranslated regions (UTRs) of mature mRNA. The 3’UTR in particular contains structural features that affect binding capacity to other RNA components, such as MicroRNA, which control mRNA localization, translation, and degradation. The degree and significance of the regulatory effects mediated by two determined variants of titin’s 3’ UTR were evaluated in Neonatal Rat Ventricular Myocyte and Human Embryonic Kidney cell lines. Recombinant plasmids to transfect these cells lines were engineered by insertion of the variant titin 3’UTR 431- and 1047-base pairs sequences into luciferase reporter vectors. Expression due to an unaltered reporter vector served as the control. Quantitative changes in luciferase activity due to the recombinants proportionally represented the effect titin’s respective 3’UTR conferred on downstream post-transcriptional expression relative to the control. The effect due to titin’s shorter 3’UTR sequence was inconclusive; however, results illustrated that titin’s longer 3’UTR sequence caused a 35 percent decrease in protein expression. Secondary structural analysis of the two sequences revealed differential folding patterns that affect the stability and degree of MicroRNA-binding within titin’s variant 3’UTR sequences.

scholarly journals CFTR Cooperative Cis-Regulatory Elements in Intestinal Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2599
Author(s):  
Mégane Collobert ◽  
Ozvan Bocher ◽  
Anaïs Le Nabec ◽  
Emmanuelle Génin ◽  
Claude Férec ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Gene Regulation ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Cftr Gene ◽  
Intestinal Cells ◽  
Cooperative Effects ◽  
Cis Acting ◽  
Study Techniques

About 8% of the human genome is covered with candidate cis-regulatory elements (cCREs). Disruptions of CREs, described as “cis-ruptions” have been identified as being involved in various genetic diseases. Thanks to the development of chromatin conformation study techniques, several long-range cystic fibrosis transmembrane conductance regulator (CFTR) regulatory elements were identified, but the regulatory mechanisms of the CFTR gene have yet to be fully elucidated. The aim of this work is to improve our knowledge of the CFTR gene regulation, and to identity factors that could impact the CFTR gene expression, and potentially account for the variability of the clinical presentation of cystic fibrosis as well as CFTR-related disorders. Here, we apply the robust GWAS3D score to determine which of the CFTR introns could be involved in gene regulation. This approach highlights four particular CFTR introns of interest. Using reporter gene constructs in intestinal cells, we show that two new introns display strong cooperative effects in intestinal cells. Chromatin immunoprecipitation analyses further demonstrate fixation of transcription factors network. These results provide new insights into our understanding of the CFTR gene regulation and allow us to suggest a 3D CFTR locus structure in intestinal cells. A better understand of regulation mechanisms of the CFTR gene could elucidate cases of patients where the phenotype is not yet explained by the genotype. This would thus help in better diagnosis and therefore better management. These cis-acting regions may be a therapeutic challenge that could lead to the development of specific molecules capable of modulating gene expression in the future.

scholarly journals A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yavor K. Bozhilov ◽  
Damien J. Downes ◽  
Jelena Telenius ◽  
A. Marieke Oudelaar ◽  
Emmanuel N. Olivier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Base Change ◽  
Dependent Manner ◽  
Globin Genes ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Single Base Change

AbstractMany single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements.

International Economic Law Tribunals and Global Social Justice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Frank J. Garcia
Keyword(s):  
International Economic ◽  
Social Justice ◽  
Social Issues ◽  
Structural Features ◽  
The Core ◽  
Economic Law ◽  
International Economic Law ◽  
The Law ◽  
Principles Of Justice ◽  
International Adjudication

Abstract International courts play a key role in the attainment of global social justice objectives. The core contributions of international adjudication to global social justice are, not surprisingly, in line with the core functions of adjudication: the enforcement of substantive rights in a setting of fair procedures. Fully realizing the potential for justice inherent in this role is limited, however, by certain institutional and structural features unique to international adjudication. This article analyzes these opportunities, challenges, and background conditions in the context of international economic law (IEL) adjudication, where the results are mixed. For example, one can see in the case of the World Trade Organization (WTO) evidence of institutional and doctrinal evolution, albeit uneven, toward more substantively progressive outcomes. In the case of the foreign investment regime, however, one can see evidence of this regime retarding global social justice rather than advancing it. This makes it all the more important that all judges and arbitrators in IEL adjudications consider carefully the interpretive, remedial, and progressive roles that principles of justice can play in adjudication, particularly in the face of any deficiencies in procedural or substantive justice in the law or forum within which they operate. The work of IEL adjudication offers a number of possible sites for interpretive practices according to principles of justice, such as the resolution of disputes involves difficult interpretive questions centered around fairness and unfairness; equality and inequality of treatment; the scope of exceptions; and the meaning of evolutionary terms. Capitalizing on these opportunities and moving IEL adjudication toward global social justice requires what effective judging always requires: a vision of the goals of the institutions and regimes in question; an understanding of the social issues the regime either was created to address or touches incidentally through its actions and externalities; careful attention to the relationships among the relevant actors and their expectations; and a sophisticated understanding of the legal context and legislative history of the law in question.

Gene-regulatory elements may change the amount, timing, or location of gene expression, cis-Regulation therapy platforms might become a gene therapy to treat many genetic diseases

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Tissue Type ◽  
Gene Promoters ◽  
Expression Levels ◽  
Cis Regulation ◽  
Gene Regulatory Elements ◽  
Gene Regulatory ◽  
Gene Expression Levels

Changes in gene expression levels above or below a particular threshold may have a dramatic impact on phenotypes, leading to a wide spectrum of human illnesses. Gene-regulatory elements, also known as cis-regulatory elements (CREs), may change the amount, timing, or location (cell/tissue type) of gene expression, whereas mutations in a gene's coding sequence may result in lower or higher gene expression levels resulting in protein loss or gain. Loss-of-function mutations in both genes produce recessive human illness, while haploinsufficient mutations in 65 genes are also known to be deleterious due to function gain, according to the ClinVar1 and ClinGen3 databases. CREs are promoters living near to a gene's transcription start site and switching it on at predefined times, places, and levels. Other distal CREs, like enhancers and silencers, are temporal and tissue-specific control promoters. Enhancers activate promoters, commonly referred to as "promoters," whereas silencers turn them off. Insulators also restrict promiscuous interactions between enhancers and gene promoters. Systematic genomic approaches can help understand the cis-regulatory circuitry of gene expression by highly detecting and functionally defining these CREs. This includes the new use of CRISPR–CRISPR-associated protein 9 (CRISPR–Cas9) and other editing approaches to discover CREs. Cis-Regulation therapy (CRT) provides many promises to heal human ailments. CRT may be used to upregulate or downregulate disease-causing genes due to lower or higher levels of expression, and it may also be used to precisely adjust the expression of genes that assist in alleviating disease features. CRT may employ proteins that generate epigenetic modifications like methylation, histone modification, or gene expression regulation looping. Weighing CRT's advantages and downsides against alternative treatment methods is crucial. CRT platforms might become a practical technique to treat many genetic diseases that now lack treatment alternatives if academics, patient communities, clinicians, regulators and industry work together.

Identification of CCNB2 expression in triple-negative breast cancer based on bioinformatics results

2021 ◽  
Author(s):  
jintao cao ◽  
SHUAI SUN ◽  
RAN LI ◽  
RUI MIN ◽  
XINGYU FAN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Triple Negative Breast Cancer ◽  
Protein Complex ◽  
Triple Negative ◽  
Expression Profiles ◽  
Pathway Enrichment Analysis ◽  
Analysis Tool ◽  
The Core ◽  
Core Genes

Abstract Background The current epidemiology shows that the incidence of breast cancer is increasing year by year and tends to be younger. Triple-negative breast cancer is the most malignant of breast cancer subtypes. The application of bioinformatics in tumor research is becoming more and more extensive. This study provided research ideas and basis for exploring the potential targets of gene therapy for triple-negative breast cancer (TNBC). Methods We analyzed three gene expression profiles (GSE64790、GSE62931、GSE38959) selected from the Gene Expression Omnibus (GEO) database. The GEO2R online analysis tool was used to screen for differentially expressed genes (DEGs) between TNBC and normal tissues. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied to identify the pathways and functional annotation of DEGs. Protein–protein interaction network of these DEGs were visualized by the Metascape gene-list analysis tool so that we could find the protein complex containing the core genes. Subsequently, we investigated the transcriptional data of the core genes in patients with breast cancer from the Oncomine database. Moreover, the online Kaplan–Meier plotter survival analysis tool was used to evaluate the prognostic value of core genes expression in TNBC patients. Finally, immunohistochemistry (IHC) was used to evaluated the expression level and subcellular localization of CCNB2 on TNBC tissues. Results A total of 66 DEGs were identified, including 33 up-regulated genes and 33 down-regulated genes. Among them, a potential protein complex containing five core genes was screened out. The high expression of these core genes was correlated to the poor prognosis of patients suffering breast cancer, especially the overexpression of CCNB2. CCNB2 protein positively expressed in the cytoplasm, and its expression in triple-negative breast cancer tissues was significantly higher than that in adjacent tissues. Conclusions CCNB2 may play a crucial role in the development of TNBC and has the potential as a prognostic biomarker of TNBC.

scholarly journals Deciphering the Enigma of the Histone H2A.Z-1/H2A.Z-2 Isoforms: Novel Insights and Remaining Questions

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1167
Author(s):  
Manjinder S. Cheema ◽  
Katrina V. Good ◽  
Bohyun Kim ◽  
Heddy Soufari ◽  
Connor O’Sullivan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Dna Damage ◽  
Chromosome Segregation ◽  
Multiple Roles ◽  
Histone H2a ◽  
The Core ◽  
Structural Differences ◽  
Functional Involvement ◽  
Insight Into

The replication independent (RI) histone H2A.Z is one of the more extensively studied variant members of the core histone H2A family, which consists of many replication dependent (RD) members. The protein has been shown to be indispensable for survival, and involved in multiple roles from DNA damage to chromosome segregation, replication, and transcription. However, its functional involvement in gene expression is controversial. Moreover, the variant in several groups of metazoan organisms consists of two main isoforms (H2A.Z-1 and H2A.Z-2) that differ in a few (3–6) amino acids. They comprise the main topic of this review, starting from the events that led to their identification, what is currently known about them, followed by further experimental, structural, and functional insight into their roles. Despite their structural differences, a direct correlation to their functional variability remains enigmatic. As all of this is being elucidated, it appears that a strong functional involvement of isoform variability may be connected to development.

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