scholarly journals Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways

2021 ◽  
Author(s):  
Teresa Davoli ◽  
Pan Cheng ◽  
Xin Zhao ◽  
Lizabeth Katsnelson ◽  
Raquel Moya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Protein Level ◽  
Gene Expression Regulation ◽  
Protein Complexes ◽  
Transcript Level ◽  
Similar Degree ◽  
Low Protein ◽  
Cellular Pathways ◽  
Migration Pathways

How cells control gene expression is a fundamental question. The relative contribution of protein-level and transcript-level regulation to this process remains unclear. Here we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate transcript and protein abundances of SCNA genes, we provide insights into the rules of gene regulation. While gene compensation mainly occurs at the protein level across tumor types, genes gained or lost show surprisingly low protein compensation in lung and high RNA compensation in colon cancer. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong transcript-level regulation. Exceptions are plasma membrane protein complexes showing a very low protein-level regulation. Strikingly, we find a strong negative association between the degree of transcript-level and protein-level regulation across genes and pathways. Moreover, genes participating in the same pathway show similar degree of transcript- and protein-level regulation. Pathways including translation, splicing and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger transcript-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve a predominant mechanism of gene regulation, possibly due to energetic constraints.

scholarly journals Synthetic protein-binding DNA sponge as a tool to tune gene expression and mitigate protein toxicity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xinyi Wan ◽  
Filipe Pinto ◽  
Luyang Yu ◽  
Baojun Wang
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Protein Binding ◽  
Gene Networks ◽  
Dynamic Range ◽  
Gene Expression Regulation ◽  
Single Layer ◽  
Regulation Mechanism ◽  
Gene Circuits ◽  
Synthetic Dna

AbstractVersatile tools for gene expression regulation are vital for engineering gene networks of increasing scales and complexity with bespoke responses. Here, we investigate and repurpose a ubiquitous, indirect gene regulation mechanism from nature, which uses decoy protein-binding DNA sites, named DNA sponge, to modulate target gene expression in Escherichia coli. We show that synthetic DNA sponges can be designed to reshape the response profiles of gene circuits, lending multifaceted tuning capacities including reducing basal leakage by >20-fold, increasing system output amplitude by >130-fold and dynamic range by >70-fold, and mitigating host growth inhibition by >20%. Further, multi-layer DNA sponges for decoying multiple regulatory proteins provide an additive tuning effect on the responses of layered circuits compared to single-layer sponges. Our work shows synthetic DNA sponges offer a simple yet generalizable route to systematically engineer the performance of synthetic gene circuits, expanding the current toolkit for gene regulation with broad potential applications.

scholarly journals Longitudinal impact on rat cardiac tissue transcriptomic profiles due to acute intratracheal inhalation exposures to isoflurane

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0257241
Author(s):  
Sung-Hyun Park ◽  
Yuting Lu ◽  
Yongzhao Shao ◽  
Colette Prophete ◽  
Lori Horton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Heart Development ◽  
Cardiac Tissue ◽  
Gene Expression Regulation ◽  
Late Onset ◽  
Global Gene Expression ◽  
Longitudinal Impact ◽  
Mitochondrial Translation ◽  
Post Exposure

Isoflurane (ISO) is a widely used inhalation anesthetic in experiments with rodents and humans during surgery. Though ISO has not been reported to impart long-lasting side effects, it is unknown if ISO can influence gene regulation in certain tissues, including the heart. Such changes could have important implications for use of this anesthetic in patients susceptible to heart failure/other cardiac abnormalities. To test if ISO could alter gene regulation/expression in heart tissues, and if such changes were reversible, prolonged, or late onset with time, SHR (spontaneously hypertensive) rats were exposed by intratracheal inhalation to a 97.5% air/2.5% ISO mixture on two consecutive days (2 hr/d). Control rats breathed filtered air only. On Days 1, 30, 240, and 360 post-exposure, rat hearts were collected and total RNA was extracted from the left ventricle for global gene expression analysis. The data revealed differentially-expressed genes (DEG) in response to ISO (compared to naïve control) at all post-exposure timepoints. The data showed acute ISO exposures led to DEG associated with wounding, local immune function, inflammation, and circadian rhythm regulation at Days 1 and 30; these effects dissipated by Day 240. There were other significantly-increased DEG induced by ISO at Day 360; these included changes in expression of genes associated with cell signaling, differentiation, and migration, extracellular matrix organization, cell-substrate adhesion, heart development, and blood pressure regulation. Examination of consistent DEG at Days 240 and 360 indicated late onset DEG reflecting potential long-lasting effects from ISO; these included DEG associated with oxidative phosphorylation, ribosome, angiogenesis, mitochondrial translation elongation, and focal adhesion. Together, the data show acute repeated ISO exposures could impart variable effects on gene expression/regulation in the heart. While some alterations self-resolved, others appeared to be long-lasting or late onset. Whether such changes occur in all rat models or in humans remains to be investigated.

Gene regulation through chromatin remodelling by members of the nuclear receptor superfamily

2000 ◽  
Vol 28 (4) ◽  
pp. 369-373 ◽  
Author(s):  
I. J. McEwan
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Transcription Factors ◽  
Thyroid Hormones ◽  
Target Gene ◽  
Protein Complexes ◽  
Nuclear Receptor Superfamily ◽  
Target Gene Expression ◽  
Dna Elements ◽  
Introductory Review

The intracellular receptors for steroid hormones, thyroid hormones, retinoids and vitamin D3 are known to bind to specific DNA elements and thus regulate target gene expression. This introductory review and the following papers address some of the mechanisms underlying this action. In particular, the ability of this family of transcription factors to recruit multi-protein complexes that have the capacity to remodel chromatin structure in order to silence or activate target gene expression is discussed.

scholarly journals Distinctive Nuclear Features of Dinoflagellates with A Particular Focus on Histone and Histone-Replacement Proteins

2018 ◽  
Vol 6 (4) ◽  
pp. 128 ◽  
Author(s):  
Sadaf Riaz ◽  
Zhenghong Sui ◽  
Zeeshan Niaz ◽  
Sohrab Khan ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Harmful Algal Blooms ◽  
Algal Blooms ◽  
Gene Expression Regulation ◽  
Expression Regulation ◽  
Histone Proteins ◽  
Methylated Dna ◽  
Low Protein ◽  
Eukaryotic Microorganisms ◽  
Nuclear Features

Dinoflagellates are important eukaryotic microorganisms that play critical roles as producers and grazers, and cause harmful algal blooms. The unusual nuclei of dinoflagellates “dinokaryon” have led researchers to investigate their enigmatic nuclear features. Their nuclei are unusual in terms of their permanently condensed nucleosome-less chromatin, immense genome, low protein to DNA ratio, guanine-cytosine rich methylated DNA, and unique mitosis process. Furthermore, dinoflagellates are the only known group of eukaryotes that apparently lack histone proteins. Over the course of evolution, dinoflagellates have recruited other proteins, e.g., histone-like proteins (HLPs), from bacteria and dinoflagellates/viral nucleoproteins (DVNPs) from viruses as histone substitutes. Expression diversity of these nucleoproteins has greatly influenced the chromatin structure and gene expression regulation in dinoflagellates. Histone replacement proteins (HLPs and DVNPs) are hypothesized to perform a few similar roles as histone proteins do in other eukaryotes, i.e., gene expression regulation and repairing DNA. However, their role in bulk packaging of DNA is not significant as low amounts of proteins are associated with the gigantic genome. This review intends to summarize the discoveries encompassing unique nuclear features of dinoflagellates, particularly focusing on histone and histone replacement proteins. In addition, a comprehensive view of the evolution of dinoflagellate nuclei is presented.

scholarly journals Evolutionary stability of topologically associating domains is associated with conserved gene regulation

2017 ◽  
Author(s):  
Jan Krefting ◽  
Miguel A. Andrade-Navarro ◽  
Jonas Ibn-Salem
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Target Genes ◽  
Gene Expression Regulation ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Building Blocks ◽  
Regulatory Sequences ◽  
Topologically Associating Domains

AbstractBackgroundThe human genome is highly organized in the three-dimensional nucleus. Chromosomes fold locally into topologically associating domains (TADs) defined by increased intra-domain chromatin contacts. TADs contribute to gene regulation by restricting chromatin interactions of regulatory sequences, such as enhancers, with their target genes. Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. However, it is not clear to which extent TAD regions are conserved in evolution and whether disruption of TADs by evolutionary rearrangements can alter gene expression.ResultsHere, we hypothesize that TADs represent essential functional units of genomes, which are selected against rearrangements during evolution. We investigate this using whole-genome alignments to identify evolutionary rearrangement breakpoints of different vertebrate species. Rearrangement breakpoints are strongly enriched at TAD boundaries and depleted within TADs across species. Furthermore, using gene expression data across many tissues in mouse and human, we show that genes within TADs have more conserved expression patterns. Disruption of TADs by evolutionary rearrangements is associated with changes in gene expression profiles, consistent with a functional role of TADs in gene expression regulation.ConclusionsTogether, these results indicate that TADs are conserved building blocks of genomes with regulatory functions that are often reshuffled as a whole instead of being disrupted by rearrangements.

scholarly journals Noncoding RNA participation in gene expression regulation in yeast Saccharomyces cerevisiae

2011 ◽  
Vol 9 (1) ◽  
pp. 3-14
Author(s):  
Olga V Kochenova
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Gene Regulation ◽  
Antisense Rna ◽  
Noncoding Rna ◽  
Gene Expression Regulation ◽  
Regulation Of Gene Expression ◽  
Yeast Genome ◽  
Yeast Saccharomyces Cerevisiae ◽  
Main Components

Saccharomyces cerevisiae lacks the main components of RNAi-dependent gene silencing. Nevertheless, regulation of gene expression in S. cerevisiae could be accomplished via some other types of noncoding RNA, particularly via antisense RNA. Although, there is a high percent of untranslated RNA in yeast genome only few evidences of noncoding RNA gene regulation exist in yeast S. cerevisiae, some of them are reviewed in the present paper. 

scholarly journals Gene Expression Changes with Minor Effects on the Population Average Have Major Effects on the Occurrence of Cells with Extreme Protein Concentrations

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Mikkel Skjoldan Svenningsen ◽  
Szabolcs Semsey ◽  
Namiko Mitarai
Keyword(s):  
Gene Expression ◽  
Protein Level ◽  
Bacterial Population ◽  
Environmental Changes ◽  
Cell Heterogeneity ◽  
Low Protein ◽  
Population Average ◽  
Highly Sensitive ◽  
Extreme Phenotypes ◽  
The Mean

ABSTRACT The cell-to-cell heterogeneity in a bacterial population provides a rich response to environmental changes and robust survival of an isogenic population. Especially, the rare, extreme phenotypes can be important for survival under transient lethal conditions. We analyze the probability of having an extremely high or low protein level in a stochastic model of gene expression. The fraction of rare state cells defined as the cells in the tails of distributions is found to be highly sensitive to small changes of the mean protein level. The result highlights the importance of relatively weak changes to the mean for the occurrence of rare phenotypes.

Role of KLF4 and KLF12 in γ-Globin Gene Regulation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4075-4075
Author(s):  
Inderdeep S Kalra ◽  
Wei Li ◽  
Shalini Muralidhar ◽  
Betty Pace
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Conflicts Of Interest ◽  
Protein Complexes ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
K562 Cells ◽  
Mrna Levels ◽  
Gene Promoters ◽  
Globin Gene Regulation

Abstract Abstract 4075 Poster Board III-1010 Kruppel-like factors (KLFs) are a family of Cys2His2 zinc-finger DNA binding proteins that regulate gene expression through CACCC/GC/GT box binding in gene promoters. The CACCC element is critical for the developmental regulation of the human γ-globin and β-globin genes and studies are being done to ferret out various factors that bind this region and modulate gene activity. We recently identified two Kruppel-like factors, KLF4 and KLF12 whose expression levels decreased based on microarray-based gene profiling, concomitantly with decreased γ-globin expression during erythroid maturation. Decreased expression of both factors was further confirmed using quantitative PCR (qPCR) analysis. KLF4 and KLF12 mRNA levels decreased 56-fold and 16-fold respectively by day 28 compared to levels in day 7 erythroid progenitors. We next determined if KLF4 and KLF12 bind the γ-globin CACC box by electrophoretic mobility shift assay (EMSA) using nuclear proteins extracted from K562 cells and a [γ-32P] labeled γ-CACC probe located between -155 to -132 relative to the γ-globin gene cap site. Three DNA-protein complexes were observed. The specificity of these interactions was confirmed by competition reactions in which preincubation with excess unlabelled γ-CACC oligonucleotide effectively abolished the formation of all DNA/protein complexes; addition of nonspecific oligonucleotide had no effect on binding activity. Addition of polyclonal KLF4 or KLF12 antibodies to the EMSA reaction resulted in a marked decrease in intensity of all DNA-protein complexes suggesting both KLF4 and KLF12 are present. Additional studies were performed to determine the effect of the known fetal hemoglobin inducer hemin on KLF gene expression in K562 cells. Hemin stimulated γ-globin transcription while increasing KLF4 and KLF12 66-fold and 4-fold respectively (p<0.05). Hemin treatment in KU812 erythroleukemia cells which actively transcribe both γ- and β-globin, also produced a 10-fold increase (p<0.05) in KLF4; KLF12 levels were not changed. Our preliminary data suggest these KLFs might play a role in γ-globin regulation. siRNA mediated gene silencing studies are underway to determine if KLF4 and/or KLF12 play a direct role in γ-globin gene regulation. This mechanism could provide important molecular targets for fetal hemoglobin reactivation. This will be highly significant towards developing therapeutic strategies for hemoglobinopathies like sickle cell anemia and β-thalassemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Nuclear retention of pre-mRNA involving Cajal bodies during meiotic prophase in plants

2021 ◽  
Author(s):  
Magda Rudzka ◽  
Malwina Hyjek-Skladanowska ◽  
Patrycja Wroblewska-Ankiewicz ◽  
Karolina Majewska ◽  
Marcin Golebiewski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Meiotic Prophase ◽  
Gene Expression Regulation ◽  
Regulation Of Gene Expression ◽  
Cajal Bodies ◽  
Nuclear Retention ◽  
Retained Introns ◽  
Generative Cells ◽  
Mature Mrnas

Gene regulation ensures that the appropriate genes are expressed at the proper times. Nuclear retention of incompletely spliced or mature mRNAs emerges as a novel, previously underappreciated layer of post-transcriptional gene regulation. Studies on this phenomenon indicated that it exerted significant impact on the regulation of gene expression by regulating export and translation delay, which allows synthesis of specific proteins in response to a stimulus, e.g. under stress conditions or at strictly controlled time points, e.g. during cell differentiation or development. Here, we found that transcription in microsporocytes, during prophase of the first meiotic division, occurs in pulsatile manner. After each pulse, the transcriptional activity is silenced, but the transcripts synthesized at this time are not exported immediately to the cytoplasm, but are retained in the nucleoplasm and Cajal bodies (CBs). In contrast to nucleoplasm, mature transcripts were not found in CBs. Only non-fully-spliced transcripts with retained introns were stored in the CBs. Retained introns are spliced at precisely defined times, and fully mature mRNAs are released into the cytoplasm, where the proteins are produced. These proteins are necessary for further cell development during meiotic prophase. Our findings provide new insight into the regulatory mechanisms of gene expression based on mRNA retention in the nucleus during the development of generative cells in plants. Similar processes were observed during spermatogenesis in animals. This indicates the existence of an evolutionarily conserved mechanism of gene expression regulation during generative cells development in Eukaryota.

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