scholarly journals Division of labor in metabolic regulation by transcription, translation, acetylation and phosphorylation

2019 ◽  
Author(s):  
Sriram Chandrasekaran
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Networks ◽  
Network Connectivity ◽  
Control Mechanisms ◽  
Post Translational Modifications ◽  
Regulatory Processes ◽  
Regulatory Architecture ◽  
A Cell ◽  
Metabolic Properties ◽  
Context Specific

AbstractThe metabolism of most organisms is controlled by a diverse cast of regulatory processes, including transcriptional regulation and post-translational modifications (PTMs). Yet how metabolic control is distributed between these regulatory processes is unknown. Here we present Comparative Analysis of Regulators of Metabolism (CAROM), an approach that compares regulators based on network connectivity, flux, and essentiality of their reaction targets. Using CAROM, we analyze transcriptome, proteome, acetylome and phospho-proteome dynamics during transition to stationary phase in E. coli and S. cerevisiae. CAROM uncovered that the targets of each regulatory process shared unique metabolic properties: growth-limiting reactions were regulated by acetylation, while isozymes and futile-cycles were preferentially regulated by phosphorylation. Reversibility, essentiality, and molecular-weight further distinguished reactions controlled through diverse mechanisms. While every enzyme can be potentially regulated by multiple mechanisms, analysis of context-specific datasets reveals a conserved partitioning of metabolic regulation based on reaction attributes.Author summaryThere are several ways to regulate an enzyme’s activity in a cell. Yet, the design principles that determine when an enzyme is regulated by transcription, translation or post-translational modifications are unknown. Each control mechanism, such as transcription, comprises several regulators that control a distinct set of targets. So far, it is unclear if similar partitioning of targets occurs at a higher level, between different control mechanisms. Here we systematically analyze patterns of metabolic regulation in model microbes. We find that five key parameters can distinguish the targets of each mechanism. These key parameters provide insights on specific roles played by each mechanism in determining overall metabolic activity. This approach may help define the basic regulatory architecture of metabolic networks.

scholarly journals Intelligent host engineering for metabolic flux optimisation in biotechnology

2021 ◽  
Vol 478 (20) ◽  
pp. 3685-3721
Author(s):  
Lachlan J. Munro ◽  
Douglas B. Kell
Keyword(s):  
Metabolic Networks ◽  
Metabolic Flux ◽  
Protein A ◽  
Search Space ◽  
Spare Capacity ◽  
Expression Levels ◽  
Regulatory Processes ◽  
A Cell ◽  
P Proteins ◽  
Combinatorial Sense

Optimising the function of a protein of length N amino acids by directed evolution involves navigating a ‘search space’ of possible sequences of some 20N. Optimising the expression levels of P proteins that materially affect host performance, each of which might also take 20 (logarithmically spaced) values, implies a similar search space of 20P. In this combinatorial sense, then, the problems of directed protein evolution and of host engineering are broadly equivalent. In practice, however, they have different means for avoiding the inevitable difficulties of implementation. The spare capacity exhibited in metabolic networks implies that host engineering may admit substantial increases in flux to targets of interest. Thus, we rehearse the relevant issues for those wishing to understand and exploit those modern genome-wide host engineering tools and thinking that have been designed and developed to optimise fluxes towards desirable products in biotechnological processes, with a focus on microbial systems. The aim throughput is ‘making such biology predictable’. Strategies have been aimed at both transcription and translation, especially for regulatory processes that can affect multiple targets. However, because there is a limit on how much protein a cell can produce, increasing kcat in selected targets may be a better strategy than increasing protein expression levels for optimal host engineering.

scholarly journals Perceptions on Regulation and Asymmetry of Information as Critical Factors in University Governance in Latin America

SAGE Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 215824402110231
Author(s):  
Juan Bautista Abello-Romero ◽  
Daniel López ◽  
Francisco Ganga ◽  
Claudio Mancilla
Keyword(s):  
Latin American ◽  
Influential Factors ◽  
Control Mechanisms ◽  
American University ◽  
American Universities ◽  
Asymmetry Of Information ◽  
Regulatory Processes ◽  
National Differences ◽  
The Board Of Directors ◽  
Latin American Universities

This article analyzes the results of an inquiry into Latin American university community members’ perceptions about regulatory processes and asymmetries of information, as influential factors in the governance of Latin American universities. It does so, by examining the national laws in Argentina, Brazil, Colombia, Chile, and Mexico. Previous studies in this continent have not considered these aspects and perspectives. Our research found significant differences between countries in terms of the Board of Directors’ capacity to act and the control mechanisms they can employ—which can be interpreted as national differences in the availability of their resources and their regulatory capacities. On the level of asymmetry of information, there are differences between countries, which depend on the position of the university members in their institutions. Thus, regulation and information are important factors when it comes to the governance of Latin American universities, and can explain its’ diversity.

scholarly journals Identifying Personalized Metabolic Signatures in Breast Cancer

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 20
Author(s):  
Priyanka Baloni ◽  
Wikum Dinalankara ◽  
John C. Earls ◽  
Theo A. Knijnenburg ◽  
Donald Geman ◽  
...  
Keyword(s):  
Drug Targets ◽  
Metabolic Networks ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Estrogen Metabolism ◽  
Acid Oxidation ◽  
A Genome ◽  
Context Specific

Cancer cells are adept at reprogramming energy metabolism, and the precise manifestation of this metabolic reprogramming exhibits heterogeneity across individuals (and from cell to cell). In this study, we analyzed the metabolic differences between interpersonal heterogeneous cancer phenotypes. We used divergence analysis on gene expression data of 1156 breast normal and tumor samples from The Cancer Genome Atlas (TCGA) and integrated this information with a genome-scale reconstruction of human metabolism to generate personalized, context-specific metabolic networks. Using this approach, we classified the samples into four distinct groups based on their metabolic profiles. Enrichment analysis of the subsystems indicated that amino acid metabolism, fatty acid oxidation, citric acid cycle, androgen and estrogen metabolism, and reactive oxygen species (ROS) detoxification distinguished these four groups. Additionally, we developed a workflow to identify potential drugs that can selectively target genes associated with the reactions of interest. MG-132 (a proteasome inhibitor) and OSU-03012 (a celecoxib derivative) were the top-ranking drugs identified from our analysis and known to have anti-tumor activity. Our approach has the potential to provide mechanistic insights into cancer-specific metabolic dependencies, ultimately enabling the identification of potential drug targets for each patient independently, contributing to a rational personalized medicine approach.

scholarly journals Mitochondria and Pharmacologic Cardiac Conditioning—At the Heart of Ischemic Injury

2021 ◽  
Vol 22 (6) ◽  
pp. 3224
Author(s):  
Christopher Lotz ◽  
Johannes Herrmann ◽  
Quirin Notz ◽  
Patrick Meybohm ◽  
Franz Kehl
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Research Field ◽  
Calcium Handling ◽  
Control Mechanisms ◽  
Intrinsic Resistance ◽  
Atp Production ◽  
Cardiac Conditioning ◽  
A Cell

Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.

Neurocognitive underpinnings of social development during childhood

2021 ◽  
Author(s):  
Nikolaus Steinbeis
Keyword(s):  
Social Control ◽  
Social Development ◽  
Middle Childhood ◽  
Behavioral Control ◽  
Control Mechanisms ◽  
Social Phenomena ◽  
Prefrontal Cortical ◽  
Regulatory Processes ◽  
Subcortical Regions ◽  
Cortical Regions

This chapter reviews the neurocognitive mechanisms underlying social development during middle childhood. The author focuses on social abilities (e.g., theory of mind and empathy) and prosocial behavior (e.g., sharing and helping). The chapter discusses studies and theories on developmental changes in these social phenomena and references evidence of neurocognitive underpinnings where available. The author argues that changes in social development during childhood can best be explained in developments in regulatory processes, such as behavioral control, emotion regulation, conflict processing, and self-other control. The author refers to this cluster of functions as social control mechanisms. Changes in these social control mechanisms are driven by the maturation of neural circuitry comprising prefrontal cortical regions and their interactions with subcortical regions. Crucially, while the neurocognitive mechanisms underlying social development are distinct for different abilities and behaviors, it appears to be domain-general processes that predominantly shape social development during middle childhood.

scholarly journals DEXOM: Diversity-based enumeration of optimal context-specific metabolic networks

2020 ◽  
Author(s):  
Pablo Rodríguez-Mier ◽  
Nathalie Poupin ◽  
Carlo de Blasio ◽  
Laurent Le Cam ◽  
Fabien Jourdan
Keyword(s):  
Metabolic Network ◽  
Metabolic Networks ◽  
Relevant Information ◽  
Experimental Information ◽  
Correct Identification ◽  
Good Representation ◽  
Metabolic State ◽  
Whole Space ◽  
Context Specific ◽  
Optimal Networks

AbstractThe correct identification of metabolic activity in tissues or cells under different environmental or genetic conditions can be extremely elusive due to mechanisms such as post-transcriptional modification of enzymes or different rates in protein degradation, making difficult to perform predictions on the basis of gene expression alone. Context-specific metabolic network reconstruction can overcome these limitations by leveraging the integration of multi-omics data into genome-scale metabolic networks (GSMN). Using the experimental information, context-specific models are reconstructed by extracting from the GSMN the sub-network most consistent with the data, subject to biochemical constraints. One advantage is that these context-specific models have more predictive power since they are tailored to the specific organism and condition, containing only the reactions predicted to be active in such context. A major limitation of this approach is that the available information does not generally allow for an unambiguous characterization of the corresponding optimal metabolic sub-network, i.e., there are usually many different sub-network that optimally fit the experimental data. This set of optimal networks represent alternative explanations of the possible metabolic state. Ignoring the set of possible solutions reduces the ability to obtain relevant information about the metabolism and may bias the interpretation of the true metabolic state. In this work, we formalize the problem of enumeration of optimal metabolic networks, we implement a set of techniques that can be used to enumerate optimal networks, and we introduce DEXOM, a novel strategy for diversity-based extraction of optimal metabolic networks. Instead of enumerating the whole space of optimal metabolic networks, which can be computationally intractable, DEXOM samples solutions from the set of optimal metabolic sub-networks maximizing diversity in order to obtain a good representation of the possible metabolic state. We evaluate the solution diversity of the different techniques using simulated and real datasets, and we show how this method can be used to improve in-silico gene essentiality predictions in Saccharomyces Cerevisiae using diversity-based metabolic network ensembles. Both the code and the data used for this research are publicly available on GitHub1.

scholarly journals Epigenomics of Plant’s Responses to Environmental Stress

2017 ◽  
Author(s):  
Suresh Kumar
Keyword(s):  
Gene Expression ◽  
Nuclear Dna ◽  
Environmental Stresses ◽  
Transcriptional Level ◽  
Epigenetic Changes ◽  
Post Translational Modifications ◽  
Genome Wide ◽  
A Cell ◽  
Non Coding Rnas ◽  
Function Activity

Genome-wide epigenetic changes in plants are being reported during the development and environmental stresses, which are often correlated with gene expression at the transcriptional level. Sum total of the biochemical changes in nuclear DNA, post-translational modifications in histone proteins and variations in the biogenesis of non-coding RNAs in a cell is known as epigenome. These changes are often responsible for variation in expression of the gene without any change in the underlying nucleotide sequence. The changes might also cause variation in chromatin structure resulting into the changes in function/activity of the genome. The epigenomic changes are dynamic with respect to the endogenous and/or environmental stimuli which affect phenotypic plasticity of the organism. Both, the epigenetic changes and variation in gene expression might return to the pre-stress state soon after withdrawal of the stress. However, a part of the epigenetic changes may be retained which is reported to play role in acclimatization, adaptation as well as in the evolutionary processes. Understanding epigenome-engineering for improved stress tolerance in plants has become essential for better utilization of the genetic factors. This review delineates the importance of epigenomics towards possible improvement of plant’s responses to environmental stresses for climate resilient agriculture.

scholarly journals Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte

2018 ◽  
Vol 19 (9) ◽  
pp. 2820 ◽  
Author(s):  
Lidia Avalle ◽  
Valeria Poli
Keyword(s):  
Energy Production ◽  
Energy Homeostasis ◽  
Multiple Roles ◽  
Pharmaceutical Companies ◽  
Signal Transducer ◽  
Post Translational Modifications ◽  
Pathological Conditions ◽  
Different Types ◽  
Tumor Transformation ◽  
Context Specific

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis.

Protein kinase C and chemical-induced abnormal palate development

2005 ◽  
Vol 24 (4) ◽  
pp. 203-214 ◽  
Author(s):  
Chada S Reddy
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Single Gene ◽  
Critical Role ◽  
Early Death ◽  
Palate Development ◽  
Kinase C ◽  
A Cell ◽  
Context Specific

The protein kinase C (PKC) family of proteins mediates the action of growth factors and other ligands by activating a network of transcription factors that bind to TRE sequences in the promoters of many genes that regulate cell proliferation, differentiation, extracellular matrix synthesis, apoptosis and others in a cell type-, isozymeand context-specific manner. The critical role of PKC in embryonic development is indicated by early death of embryos in which one or more of these isozymes are inactivated. Our studies together with others show that palatal PKC signalling is functional and may be essential for normal palate development. Although single gene knockouts have failed to exhibit the cleft palate (CP) phenotype, owing to compensation by other kinases, many chemicals including the mycotoxin, secalonic acid D, disrupt palatal PKC signalling leading to altered palatal mesenchymal gene expression. The potential relevance of such effects to chemical-induced CP is discussed.

scholarly journals Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 723 ◽  
Author(s):  
Roberta Noberini ◽  
Camilla Restellini ◽  
Evelyn Oliva Savoia ◽  
Francesco Raimondi ◽  
Lavinia Ghiani ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Culture Conditions ◽  
Clinical Samples ◽  
Post Translational Modifications ◽  
A Cell ◽  
Cancer Types ◽  
Histone Modifying Enzymes

Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer.

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