scholarly journals Mutational Signatures as Sensors of Environmental Exposures: Role of Smoking in COVID-19 Vulnerabilities

2021 ◽  
Author(s):  
Yoo-Ah Kim ◽  
Ermin Hodzic ◽  
Ariella Saslafsky ◽  
Damian Wojtowicz ◽  
Bayarbaatar Amgalan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Environmental Factors ◽  
Disease Progression ◽  
Environmental Exposures ◽  
Biological Processes ◽  
Mutational Signatures ◽  
Mutational Signature ◽  
The Impact ◽  
Pathway Level

Background: Environmental exposures such as smoking are widely recognized risk factors in the emergence of lung diseases such as lung cancer and acute respiratory distress syndrome (ARDS). However, the strength of environmental exposures is difficult to measure, making it challenging to understand their impacts. On the other hand, some COVID-19 patients develop ARDS in an unfavorable disease progression and smoking has been suggested as a potential risk factor among others. Yet initial studies on COVID-19 cases reported contradictory results on the effects of smoking on the disease. Some suggest that smoking might have a protective effect against it while other studies report an increased risk. A better understanding of how the exposure to smoking and other environmental factors affect biological processes relevant to SARS-CoV-2 infection and unfavorable disease progression is needed. Approach: In this study, we utilize mutational signatures associated with environmental factors as sensors of their exposure level. Many environmental factors including smoking are mutagenic and leave characteristic patterns of mutations, called mutational signatures, in affected genomes. We postulated that analyzing mutational signatures, combined with gene expression, can shed light on the impact of the mutagenic environmental factors to the biological processes. In particular, we utilized mutational signatures from lung adenocarcinoma (LUAD) data set collected in TCGA to investigate the role of environmental factors in COVID-19 vulnerabilities. Integrating mutational signatures with gene expression in normal tissues and using a pathway level analysis, we examined how the exposure to smoking and other mutagenic environmental factors affects the infectivity of the virus and disease progression. Results: By delineating changes associated with smoking in pathway-level gene expression and cell type proportions, our study demonstrates that mutational signatures can be utilized to study the impact of exogenous mutagenic factors on them. Consistent with previous findings, our analysis showed that smoking mutational signature (SBS4) is associated with activation of cytokines mediated singling pathways, leading to inflammatory responses. Smoking related changes in cell composition were also observed, including the correlation of SBS4 with the expansion of goblet cells. On the other hand, increased basal cells and decreased ciliated cells in proportion were associated with the strength of a different mutational signature (SBS5), which is present abundantly but not exclusively in smokers. In addition, we found that smoking increases the expression levels of genes that are upregulated in severe COVID-19 cases. Jointly, these results suggest an unfavorable impact of smoking on the disease progression and also provide novel findings on how smoking impacts biological processes in lung.

scholarly journals Optimizing expression quantitative trait locus mapping workflows for single-cell studies

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anna S. E. Cuomo ◽  
Giordano Alvari ◽  
Christina B. Azodi ◽  
Davis J. McCarthy ◽  
Marc Jan Bonder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait Locus ◽  
Single Cell ◽  
Quantitative Trait ◽  
Cell Types ◽  
Expression Quantitative Trait Locus ◽  
Eqtl Mapping ◽  
Trait Locus ◽  
The Impact

Abstract Background Single-cell RNA sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states and promises to improve our understanding of genetic regulation across tissues in both health and disease. Results While previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimize sc-eQTL mapping. Here, we evaluate the role of different normalization and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches. Conclusion We provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.

Speciation and changes in male gene expression in Drosophila

Genome ◽  
2020 ◽  
pp. 1-11
Author(s):  
Bahar Patlar ◽  
Alberto Civetta
Keyword(s):  
Gene Expression ◽  
Reproductive Isolation ◽  
Potential Role ◽  
Regulation Of Gene Expression ◽  
Drosophila Model ◽  
Depth Analysis ◽  
The Impact ◽  
Plastic Responses ◽  
Male Gene

It has long been acknowledged that changes in the regulation of gene expression may account for major organismal differences. However, we still do not fully understand how changes in gene expression evolve and how do such changes influence organisms’ differences. We are even less aware of the impact such changes might have in restricting gene flow between species. Here, we focus on studies of gene expression and speciation in the Drosophila model. We review studies that have identified gene interactions in post-mating reproductive isolation and speciation, particularly those that modulate male gene expression. We also address studies that have experimentally manipulated changes in gene expression to test their effect in post-mating reproductive isolation. We highlight the need for a more in-depth analysis of the role of selection causing disrupted gene expression of such candidate genes in sterile/inviable hybrids. Moreover, we discuss the relevance to incorporate more routinely assays that simultaneously evaluate the potential effects of environmental factors and genetic background in modulating plastic responses in male genes and their potential role in speciation.

scholarly journals Cryptic Transcription and Early Termination in the Control of Gene Expression

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Jessie Colin ◽  
Domenico Libri ◽  
Odil Porrua
Keyword(s):  
Gene Expression ◽  
Rna Polymerase Ii ◽  
Regulatory Function ◽  
Large Set ◽  
Control Of Gene Expression ◽  
Alternative Transcription ◽  
Cryptic Transcription ◽  
Nuclear Exosome ◽  
The Impact

Recent studies on yeast transcriptome have revealed the presence of a large set of RNA polymerase II transcripts mapping to intergenic and antisense regions or overlapping canonical genes. Most of these ncRNAs (ncRNAs) are subject to termination by the Nrd1-dependent pathway and rapid degradation by the nuclear exosome and have been dubbed cryptic unstable transcripts (CUTs). CUTs are often considered as by-products of transcriptional noise, but in an increasing number of cases they play a central role in the control of gene expression. Regulatory mechanisms involving expression of a CUT are diverse and include attenuation, transcriptional interference, and alternative transcription start site choice. This review focuses on the impact of cryptic transcription on gene expression, describes the role of the Nrd1-complex as the main actor in preventing nonfunctional and potentially harmful transcription, and details a few systems where expression of a CUT has an essential regulatory function. We also summarize the most recent studies concerning other types of ncRNAs and their possible role in regulation.

Gene–environment interplay in the etiology of psychosis

2018 ◽  
Vol 48 (12) ◽  
pp. 1925-1936 ◽  
Author(s):  
Alyson Zwicker ◽  
Eileen M. Denovan-Wright ◽  
Rudolf Uher
Keyword(s):  
Environmental Factors ◽  
Genetic Risk ◽  
Environmental Exposures ◽  
Response To Treatment ◽  
Human Potential ◽  
Specific Gene ◽  
Environment Interaction ◽  
Gene Environment ◽  
Increased Risk ◽  
The Impact

AbstractSchizophrenia and other types of psychosis incur suffering, high health care costs and loss of human potential, due to the combination of early onset and poor response to treatment. Our ability to prevent or cure psychosis depends on knowledge of causal mechanisms. Molecular genetic studies show that thousands of common and rare variants contribute to the genetic risk for psychosis. Epidemiological studies have identified many environmental factors associated with increased risk of psychosis. However, no single genetic or environmental factor is sufficient to cause psychosis on its own. The risk of developing psychosis increases with the accumulation of many genetic risk variants and exposures to multiple adverse environmental factors. Additionally, the impact of environmental exposures likely depends on genetic factors, through gene–environment interactions. Only a few specific gene–environment combinations that lead to increased risk of psychosis have been identified to date. An example of replicable gene–environment interaction is a common polymorphism in theAKT1gene that makes its carriers sensitive to developing psychosis with regular cannabis use. A synthesis of results from twin studies, molecular genetics, and epidemiological research outlines the many genetic and environmental factors contributing to psychosis. The interplay between these factors needs to be considered to draw a complete picture of etiology. To reach a more complete explanation of psychosis that can inform preventive strategies, future research should focus on longitudinal assessments of multiple environmental exposures within large, genotyped cohorts beginning early in life.

P–181 Morphine regulates BMP4 growth factor and is involved in in-vitro early embryo development and PGCs formation

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
I Muñoa ◽  
M Araolaza-Lasa ◽  
I Urizar-Arenaza ◽  
M Gianzo Citores ◽  
N Subiran Ciudad
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Environmental Factors ◽  
Embryo Development ◽  
Early Embryo ◽  
Epigenetic Changes ◽  
Morphine Treatment ◽  
Early Embryo Development

Abstract Study question To elucidate if morphine can alter embryo development. Summary answer Chronic morphine treatment regulates BMP4 growth factor, in terms of gene expression and H3K27me3 enrichment and promotes in-vitro blastocysts development and PGC formation. What is known already BMP4 is a member of the bone morphogenetic protein family, which acts mainly through SMAD dependent pathway, to play an important role in early embryo development. Indeed, BMP4 enhances pluripotency in mouse embryonic stem cells (mESCs) and, specifically, is involved in blastocysts formation and primordial germ cells (PGCs) generation. Although, external morphine influence has been previously reported on the early embryo development, focus on implantation and uterus function, there is a big concern in understanding how environmental factors can cause stable epigenetic changes, which could be maintained during development and lead to health problems. Study design, size, duration First, OCT4-reported mESCs were chronically treated with morphine during 24h, 10–5mM. After morphine removal, mESCs were collected for RNA-seq and H3K27me3 ChIP-seq study. To elucidate the role of morphine in early embryo development, two cell- embryos stage were chronically treated with morphine for 24h and in-vitro cultured up to the blastocyst stage in the absence of morphine. Furthermore, after morphine treatment mESCs were differentiated to PGCs, to elucidate the role of morphine in PGC differentiation. Participants/materials, setting, methods Transcriptomic analyses and H3K27me3 genome wide distribution were carried out by RNA-Sequencing and Chip-Sequencing respectively. Validations were performed by RNA-RT-qPCR and Chip-RT-qPCR. Main results and the role of chance Dynamic transcriptional analyses identified a total of 932 differentially expressed genes (DEGs) after morphine treatment on mESCs, providing strong evidence of a transcriptional epigenetic effect induced by morphine. High-throughput screening approaches showed up Bmp4 as one of the main morphine targets on mESCs. Morphine caused an up-regulation of Bmp4 gene expression together with a decrease of H3K27me3 enrichment at promoter level. However, no significant differences were observed on gene expression and H3K27me3 enrichment on BMP4 signaling pathway components (such as Smad1, Smad4, Smad5, Smad7, Prdm1 and Prmd14) after morphine treatment. On the other hand, the Bmp4 gene expression was also up-regulated in in-vitro morphine treated blastocyst and in-vitro morphine treated PGCs. These results were consistent with the increase in blastocyst rate and PGC transformation rate observed after morphine chronic treatment. Limitations, reasons for caution To perform the in-vitro analysis. Further studies are needed to describe the whole signaling pathways underlying BMP4 epigenetic regulation after morphine treatment. Wider implications of the findings: Our findings confirmed that mESCs and two-cell embryos are able to memorize morphine exposure and promote both blastocyst development and PGCs formation through potentially BMP4 epigenetic regulation. These results provide insights understanding how environmental factors can cause epigenetic changes during the embryo development, leading to alterations and producing health problems/diseases Trial registration number Not applicable

Abstract MP204: Pyruvate Dehydrogenase Kinase Isozyme Specific Regulation Of Protein Acetylation In Cardiac Tissue

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Chae-Myeong Ha ◽  
Adam R Wende
Keyword(s):  
Gene Expression ◽  
Heart Disease ◽  
Knockout Mice ◽  
Pyruvate Dehydrogenase ◽  
Cardiac Tissue ◽  
Cell Protein ◽  
Protein Acetylation ◽  
Acetyl Coa ◽  
The Impact

Heart disease is the number one cause of death in developed countries. Metabolic diseases influence the severity of heart disease linked to risk factors which are thought to alter epigenetic mechanisms. Pyruvate dehydrogenase (PDH) kinases (PDK), which phosphorylate and reduce the activity of PDH the nexus of glucose oxidation and fatty acid oxidation are sensitive to metabolic status. Four isozymes of PDK (PDK1-4) exist with PDK2 and PDK4 as the major regulators in cardiac tissue. Owing to the role of PDH in regulating pyruvate to acetyl-CoA, we hypothesized that PDK inhibition may regulate protein acetylation through increasing acetyl-CoA because of PDH activation leading to post-translational modifications both directly to proteins in metabolic pathways as well as to histones associated with the genes encoding them. To test this, we utilized PDK2 germline knockout mice (P2KO), PDK4 germline knockout mice (P4KO), and PDK2 and PDK4 double knockout (DKO) mice for molecular analysis. Our results identify a novel increase in whole-cell protein acetylation in P2KO left ventricle tissue (LV). However, protein acetylation in P4KO LV was not changed compared to WT mice. The most robust protein acetylation was observed in the DKO LV. Furthermore, when we explored sub-cellular distribution of protein acetylation, the greatest increases were found on cytoplasmic proteins, with moderate changes in mitochondrial proteins. We also found PDK2 ablation induces histone H3 acetylation, which may also lead to changes in gene expression. Moreover, this protein acetylation in P2KO and DKO was not seen in other tissues examined (e.g., liver, skeletal muscle). The hyperacetylation is robust in male LV compared to female LV. In conclusion, our study supports a novel protein acetylation mechanism that is both tissue and PDK isozyme specific highlighting the role of PDK2, which is relatively understudied compared to PDK4 in heart disease. Further study will evaluate if the hyperacetylation has a beneficial effect in various heart disease settings as well as identify the impact on changes in gene expression. This study supports PDK isozyme-specific inhibition strategies will be required to develop therapeutic targets of cardiovascular disease with metabolic inflexibility.

scholarly journals Direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

2019 ◽  
Vol 116 (20) ◽  
pp. 9893-9902 ◽  
Author(s):  
Christopher M. Uyehara ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Transcriptional Responses ◽  
Enhancer Activity ◽  
Developmental Transitions ◽  
Experimental Systems ◽  
The Impact

The ecdysone pathway was among the first experimental systems employed to study the impact of steroid hormones on the genome. In Drosophila and other insects, ecdysone coordinates developmental transitions, including wholesale transformation of the larva into the adult during metamorphosis. Like other hormones, ecdysone controls gene expression through a nuclear receptor, which functions as a ligand-dependent transcription factor. Although it is clear that ecdysone elicits distinct transcriptional responses within its different target tissues, the role of its receptor, EcR, in regulating target gene expression is incompletely understood. In particular, EcR initiates a cascade of transcription factor expression in response to ecdysone, making it unclear which ecdysone-responsive genes are direct EcR targets. Here, we use the larval-to-prepupal transition of developing wings to examine the role of EcR in gene regulation. Genome-wide DNA binding profiles reveal that EcR exhibits widespread binding across the genome, including at many canonical ecdysone response genes. However, the majority of its binding sites reside at genes with wing-specific functions. We also find that EcR binding is temporally dynamic, with thousands of binding sites changing over time. RNA-seq reveals that EcR acts as both a temporal gate to block precocious entry to the next developmental stage as well as a temporal trigger to promote the subsequent program. Finally, transgenic reporter analysis indicates that EcR regulates not only temporal changes in target enhancer activity but also spatial patterns. Together, these studies define EcR as a multipurpose, direct regulator of gene expression, greatly expanding its role in coordinating developmental transitions.

scholarly journals The Role of Counter-Ions in Peptides—An Overview

2020 ◽  
Vol 13 (12) ◽  
pp. 442
Author(s):  
Karol Sikora ◽  
Maciej Jaśkiewicz ◽  
Damian Neubauer ◽  
Dorian Migoń ◽  
Wojciech Kamysz
Keyword(s):  
Mobile Phase ◽  
Analytical Techniques ◽  
Drug Formulation ◽  
Biological Processes ◽  
Multiple Functions ◽  
Mobile Phase Additives ◽  
Counter Ions ◽  
Living Organisms ◽  
The Impact

Peptides and proteins constitute a large group of molecules that play multiple functions in living organisms. In conjunction with their important role in biological processes and advances in chemical approaches of synthesis, the interest in peptide-based drugs is still growing. As the side chains of amino acids can be basic, acidic, or neutral, the peptide drugs often occur in the form of salts with different counter-ions. This review focuses on the role of counter-ions in peptides. To date, over 60 peptide-based drugs have been approved by the FDA. Based on their area of application, biological activity, and results of preliminary tests they are characterized by different counter-ions. Moreover, the impact of counter-ions on structure, physicochemical properties, and drug formulation is analyzed. Additionally, the application of salts as mobile phase additives in chromatographic analyses and analytical techniques is highlighted.

Connected through the force: mechanical signals in plant development

2019 ◽  
Vol 70 (14) ◽  
pp. 3507-3519 ◽  
Author(s):  
Benoit Landrein ◽  
Gwyneth Ingram
Keyword(s):  
Gene Expression ◽  
Plant Development ◽  
Growth And Development ◽  
Biological Processes ◽  
Plant Morphogenesis ◽  
Mechanical Signals ◽  
Physical Forces ◽  
Multicellular Organisms ◽  
Biochemical Signals

Abstract As multicellular organisms, plants acquire characteristic shapes through a complex set of biological processes known as morphogenesis. Biochemical signalling underlies much of development, as it allows cells to acquire specific identities based on their position within tissues and organs. However, as growing physical structures, plants, and their constituent cells, also experience internal and external physical forces that can be perceived and can influence key processes such as growth, polarity, and gene expression. This process, which adds another layer of control to growth and development, has important implications for plant morphogenesis. This review provides an overview of recent research into the role of mechanical signals in plant development and aims to show how mechanical signalling can be used, in concert with biochemical signals, as a cue allowing cells and tissues to coordinate their behaviour and to add robustness to developmental processes.

scholarly journals Regulation of mRNA cap methylation

2009 ◽  
Vol 425 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Victoria H. Cowling
Keyword(s):  
Gene Expression ◽  
Cell Viability ◽  
Nuclear Export ◽  
Present Review ◽  
Biological Processes ◽  
Experimental Systems ◽  
Efficient Gene ◽  
Cellular Mrnas ◽  
Eukaryotic Organisms ◽  
The Impact

The 7-methylguanosine cap added to the 5′ end of mRNA is essential for efficient gene expression and cell viability. Methylation of the guanosine cap is necessary for the translation of most cellular mRNAs in all eukaryotic organisms in which it has been investigated. In some experimental systems, cap methylation has also been demonstrated to promote transcription, splicing, polyadenylation and nuclear export of mRNA. The present review discusses how the 7-methylguanosine cap is synthesized by cellular enzymes, the impact that the 7-methylguanosine cap has on biological processes, and how the mRNA cap methylation reaction is regulated.

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