scholarly journals Regulatory mechanisms of gene expression: complexity with elements of deterministic chaos.

2006 ◽  
Vol 53 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Jolanta Jura ◽  
Paulina Wegrzyn ◽  
Jacek Jura ◽  
Aleksander Koj
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Linear Models ◽  
Nonlinear Models ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Deterministic Chaos ◽  
Mrna Translation ◽  
Hard Determinism ◽  
Complex Relationships

Linear models based on proportionality between variables have been commonly applied in biology and medicine but in many cases they do not describe correctly the complex relationships of living organisms and now are being replaced by nonlinear theories of deterministic chaos. Recent advances in molecular biology and genome sequencing may lead to a simplistic view that all life processes in a cell, or in the whole organism, are strictly and in a linear fashion controlled by genes. In reality, the existing phenotype arises from a complex interaction of the genome and various environmental factors. Regulation of gene expression in the animal organism occurs at the level of epigenetic DNA modification, RNA transcription, mRNA translation, and many additional alterations of nascent proteins. The process of transcription is highly complicated and includes hundreds of transcription factors, enhancers and silencers, as well as various species of low molecular mass RNAs. In addition, alternative splicing or mRNA editing can generate a family of polypeptides from a single gene. Rearrangement of coding DNA sequences during somatic recombination is the source of great variability in the structure of immunoglobulins and some other proteins. The process of rearrangement of immunoglobulin genes, or such phenomena as parental imprinting of some genes, appear to occur in a random fashion. Therefore, it seems that the mechanism of genetic information flow from DNA to mature proteins does not fit the category of linear relationship based on simple reductionism or hard determinism but would be probably better described by nonlinear models, such as deterministic chaos.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

scholarly journals Unified AI framework to uncover deep interrelationships between gene expression and Alzheimer’s disease neuropathologies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicasia Beebe-Wang ◽  
Safiye Celik ◽  
Ethan Weinberger ◽  
Pascal Sturmfels ◽  
Philip L. De Jager ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Neural Networks ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Deep Neural Networks ◽  
Linear Models ◽  
Joint Analysis ◽  
Analysis Framework ◽  
Complex Relationships

AbstractDeep neural networks (DNNs) capture complex relationships among variables, however, because they require copious samples, their potential has yet to be fully tapped for understanding relationships between gene expression and human phenotypes. Here we introduce an analysis framework, namely MD-AD (Multi-task Deep learning for Alzheimer’s Disease neuropathology), which leverages an unexpected synergy between DNNs and multi-cohort settings. In these settings, true joint analysis can be stymied using conventional statistical methods, which require “harmonized” phenotypes and tend to capture cohort-level variations, obscuring subtler true disease signals. Instead, MD-AD incorporates related phenotypes sparsely measured across cohorts, and learns interactions between genes and phenotypes not discovered using linear models, identifying subtler signals than cohort-level variations which can be uniquely recapitulated in animal models and across tissues. We show that MD-AD exploits sex-specific relationships between microglial immune response and neuropathology, providing a nuanced context for the association between inflammatory genes and Alzheimer’s Disease.

Mammalian genome evolution as a result of epigenetic regulation of transposable elements

2014 ◽  
Vol 5 (3) ◽  
pp. 183-194 ◽  
Author(s):  
Reuben M. Buckley ◽  
David L. Adelson
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Epigenetic Regulation ◽  
Dna Sequences ◽  
Defense Mechanisms ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Epigenetic Marks ◽  
Rna Molecules ◽  
Mammalian Genomes

AbstractTransposable elements (TEs) make up a large proportion of mammalian genomes and are a strong evolutionary force capable of rewiring regulatory networks and causing genome rearrangements. Additionally, there are many eukaryotic epigenetic defense mechanisms able to transcriptionally silence TEs. Furthermore, small RNA molecules that target TE DNA sequences often mediate these epigenetic defense mechanisms. As a result, epigenetic marks associated with TE silencing can be reestablished after epigenetic reprogramming – an event during the mammalian life cycle that results in widespread loss of parental epigenetic marks. Furthermore, targeted epigenetic marks associated with TE silencing may have an impact on nearby gene expression. Therefore, TEs may have driven species evolution via their ability to heritably alter the epigenetic regulation of gene expression in mammals.

scholarly journals Generally applicable transcriptome-wide analysis of translational efficiency using anota2seq

2017 ◽  
Author(s):  
Christian Oertlin ◽  
Julie Lorent ◽  
Valentina Gandin ◽  
Carl Murie ◽  
Laia Masvidal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Analytical Methods ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Translation Regulation ◽  
Translational Efficiency ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Mtor Inhibition

ABSTRACTmRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated results in various disorders. Optimal and universally applicable analytical methods to study transcriptome-wide changes in translational efficiency are therefore critical for understanding the complex role of translation regulation under physiological and pathological conditions. Techniques used to interrogate translatomes, including polysome- and ribosome-profiling, require adjustment for changes in total mRNA levels to capture bona fide alterations in translational efficiency. Herein, we present the anota2seq algorithm for such analysis using data from ribosome- or polysome-profiling quantified by DNA-microarrays or RNA sequencing, which outperforms current methods for identification of changes in translational efficiency. In contrast to available analytical methods, anota2seq also allows capture of an underappreciated mode for regulation of gene expression whereby translation acts as a buffering mechanism which maintains constant protein levels despite fluctuations in mRNA levels (“translational buffering”). Application of anota2seq shows that insulin affects gene expression at multiple levels, in a largely mTOR-dependent manner. Moreover, insulin induces levels of a subset of mRNAs independently of mTOR that undergo translational buffering upon mTOR inhibition. Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes and enables studies of translational buffering which represents an unexplored mechanism for regulating of gene expression.

scholarly journals Bases of antisense IncRNA-associated regulation of gene expression in fission yeast

2017 ◽  
Author(s):  
Maxime Wery ◽  
Camille Gautier ◽  
Marc Descrimes ◽  
Mayuko Yoda ◽  
Valérie Migeot ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Fission Yeast ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Model Organisms ◽  
Critical Threshold ◽  
Multiple Model ◽  
Regulate Gene Expression ◽  
Regulate Gene

ABSTRACTAntisense (as)lncRNAs can regulate gene expression but the underlying mechanisms and the different cofactors involved remain unclear. Using Native Elongating Transcript sequencing, here we show that stabilization of antisense Exo2-sensitivite IncRNAs (XUTs) results in the attenuation, at the nascent transcription level, of a subset of highly expressed genes displaying prominent promoter-proximal nucleosome depletion and histone acetylation. Mechanistic investigations on the catalase genectt1revealed that its induction following oxidative stress is impaired in Exo2-deficient cells, correlating with the accumulation of an asXUT. Interestingly, expression of this asXUT was also activated in wild-type cells upon oxidative stress, concomitant toctt1induction, indicating a potential attenuation feedback. This attenuation correlates with asXUT abundance, it is transcriptional, characterized by low RNAPII-ser5 phosphorylation, and it requires an histone deacetylase activity and the conserved Set2 histone methyltransferase. Finally, we identified Dicer as another RNA processing factor acting onctt1induction, but independently of Exo2. We propose that asXUTs could modulate the expression of their paired-sense genes when it exceeds a critical threshold, using a conserved mechanism independent of RNAi.AUTHOR SUMMARYExamples of regulatory antisense (as)lncRNAs acting on gene expression have been reported in multiple model organisms. However, despite their regulatory importance, aslncRNAs have been poorly studied, and the molecular bases for aslncRNAs-mediated regulation remain incomplete. One reason for the lack of global information on aslncRNAs appears to be their low cellular abundance. Indeed, our previous studies in budding and fission yeasts revealed that aslncRNAs are actively degraded by the Xrn1/Exo2-dependent cytoplasmic 5′-3′ RNA decay pathway. Using a combination of single-gene and genome-wide analyses in fission yeast, here we report that the stabilization of a set of Exo2-sensitive aslncRNAs correlates with attenuation of paired-sense genes transcription. Our work provides fundamental insights into the mechanism by which aslncRNAs could regulate gene expression. It also highlights for the first time that the level of sense gene transcription and the presence of specific chromatin features could define the potential of aslncRNA-mediated attenuation, raising the idea that aslncRNAs only attenuate those genes with expression levels above a “regulatory threshold”. This opens novel perspectives regarding what the potential determinants of aslncRNA-dependent regulation, as previous models in budding yeast rather proposed that aslncRNA-mediated repression is restricted to lowly expressed genes.

scholarly journals Genomic methods in profiling DNA accessibility and factor localization

2019 ◽  
Vol 28 (1) ◽  
pp. 69-85 ◽  
Author(s):  
David C. Klein ◽  
Sarah J. Hainer
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Protein Localization ◽  
Regulation Of Gene Expression ◽  
Regulatory Regions ◽  
Histone Proteins ◽  
Putative Gene ◽  
Factor Binding ◽  
Advantages And Disadvantages ◽  
Dna Accessibility

AbstractRecent advancements in next-generation sequencing technologies and accompanying reductions in cost have led to an explosion of techniques to examine DNA accessibility and protein localization on chromatin genome-wide. Generally, accessible regions of chromatin are permissive for factor binding and are therefore hotspots for regulation of gene expression; conversely, genomic regions that are highly occupied by histone proteins are not permissive for factor binding and are less likely to be active regulatory regions. Identifying regions of differential accessibility can be useful to uncover putative gene regulatory regions, such as enhancers, promoters, and insulators. In addition, DNA-binding proteins, such as transcription factors that preferentially bind certain DNA sequences and histone proteins that form the core of the nucleosome, play essential roles in all DNA-templated processes. Determining the genomic localization of chromatin-bound proteins is therefore essential in determining functional roles, sequence motifs important for factor binding, and regulatory networks controlling gene expression. In this review, we discuss techniques for determining DNA accessibility and nucleosome positioning (DNase-seq, FAIRE-seq, MNase-seq, and ATAC-seq) and techniques for detecting and functionally characterizing chromatin-bound proteins (ChIP-seq, DamID, and CUT&RUN). These methods have been optimized to varying degrees of resolution, specificity, and ease of use. Here, we outline some advantages and disadvantages of these techniques, their general protocols, and a brief discussion of their development. Together, these complimentary approaches have provided an unparalleled view of chromatin architecture and functional gene regulation.

scholarly journals Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Chiara Naro ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Posttranslational Modifications ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Eukaryotic Cells ◽  
Macromolecular Complex

Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted bycis-acting RNA sequence elements andtrans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation.

scholarly journals In Search of Selectivity: Design, Synthesis, and Biological Evaluation of New Classes of HDAC Inhibitors

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 63
Author(s):  
L. M. Viranga Tillekeratne ◽  
Ayad Ayad Al-Hamashi ◽  
Samkeliso Dlamini ◽  
William Taylor ◽  
Radhika Koranne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Metal Binding ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Epigenetic Modulation

Epigenetic regulation of gene expression without changing DNA sequences is a promising strategy in developing therapeutic agents for human diseases, especially cancer. Histone deacetylases (HDACs) are a family of enzymes involved in epigenetic modulation of gene expression by chromatin remodeling. Deacetylation of the lysine side chains of histones by HDAC proteins renders DNA transcriptionally inactive, resulting in the inhibition of expression of tumor suppressor genes, leading to tumorigenesis and tumor progression. Therefore, inhibiting HDAC enzymes has become an attractive strategy to modulate gene expression as a strategy for developing anticancer drugs. There are currently four FDA-approved cancer drugs in clinical use, and many more are in different stages of clinical trials. However, their clinical utility is limited due to undesirable side effects, mainly attributed to their lack of selectivity and the presence of a hydroxamic acid moiety as the metal-binding group. There are eighteen different isoforms of HDACs belonging to four classes that have been identified in humans. A major challenge in HDAC inhibitor development is how to make them selective for these HDAC isoforms and classes. We report the design and synthesis of new classes of HDAC inhibitors and the evaluation of their anticancer activity and selectivity.

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