Epigenetic codes in cognition and behaviour.
TL;DR: Recent findings on the role and mechanisms of epigenetic codes in the brain are described, and their implication in synaptic plasticity, cognitive functions and psychiatric disorders are discussed.
About: This article is published in Behavioural Brain Research.The article was published on 2008-09-01. It has received 260 citations till now. The article focuses on the topics: Epigenetic code & Epigenetics.
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Dissertation•
27 Oct 2015
TL;DR: It is proposed that the interplay of metabolic burden and selection pressure at an early time point of cultivation plays an important role in cell line development.
Abstract: The CHO-K1 cell line is the most common expression system for therapeutic proteins in the pharmaceutical industry. Due to the nature of economics, the cell lines and the vector design are subject to constant change to increase product quality and quantity. During the cultivation, the production cell lines are susceptible to decreasing productivity over time. Often the loss of production can be associated with a reduction of copy number and the silencing of transgenes. During cell line development, the most promising cell lines are cultivated in large batch culture. Consequently, the loss of a stable production cell line can be very cost-intensive. For this reason I developed different strategies to avoid a reduced productivity. Instability of production cell lines can be predicted by the degree of CpG methylation of the driving promoter. Considering that the DNA methylation is at the end of an epigenetic cascade and associated with the maintenance of the repressive state, I investigated the upstream signals of histone modifications with the assumption to obtain a higher predictive power of production instability. For this reason I performed a chromatin immunoprecipitation of the histone modifications H3K9me3 and H3K27me3 as repressive signals and H3ac as well as H3K4me3 as active marks. The accumulations of those signals were measured close to the hCMV-MIE at the beginning of the cultivation and were then compared with the loss of productivity over two month. I found that the degree of the H3 acetylation (H3ac) correlated best with the production stability. Furthermore I was able to identify an H3ac threshold to exclude most of the unstable producers.
In the second project I aimed to improve the vector design by considering epigenetic mechanisms. To this end I designed on the one hand a target-oriented histone acetyltransferase to enforce an open and active chromatin status at the transgene. On the other hand I point-mutated methylation-susceptible CpGs within the hCMV-MIE to impede the maintenance of inactive heterochromatin formation. Remarkably, the C to G mutation located 179 bp upstream of transcription start site resulted in very stable antibody producing cell lines. In addition, the examination of cell pools expressing eGFP showed that G-179 promoter variants were less prone to a general methylation and gene amplification, which illustrates the dominating effect in epigenetic mechanisms of one single CpG.
The last project was performed to localize stable integration sites within the CHO-K1 genome. In so doing I could show that the transfection leads predominantly to integration into inactive regions. Furthermore I identified promising integration sites with a high potential to induce stable expression. However, those results are preliminary and must be viewed with caution. Further examination needs to be done to confirm these results.
Considering the results of all three projects, I propose that the interplay of metabolic burden and selection pressure at an early time point of cultivation plays an important role in cell line development. Small alterations of selection pressure can lead to a decisive change of cell properties. Therefore, stable cells are less susceptible than weak producers. The increase of selection pressure leads to compensatory effect by gene amplification in the instable cell lines. The resulting adjustment of productivity masks the truly stable cells, which precludes the selection of the right cell lines. For this reason the selection pressure, the copy number as well as the growth rate should be considered to minimize repressive effects.
1 citations
TL;DR: It is proposed that, when trying to deal with challenging situations, stereotypies might initially help animals to cope and it is possible that reported neuroanatomical changes are an effect of the stereotypy rather than a cause.
Abstract: Simple Summary Herein, we propose that there should be discussion about the function and effects of stereotypies in relation to the time during which they are shown. In the first stages, stereotypies may help animals deal with challenges. However, behavior can potentially alter the brain, impairing its function due the absence of a diverse repertory, and change brain connections, neurophysiology and later neuroanatomy. The neuroanatomical changes in individuals showing stereotypies could be an effect rather than a cause of the stereotypy. As a consequence, studies showing different outcomes for animal welfare from stereotypy expression could be due to variation in a timeline of expression. Stereotypies are widely used as an animal welfare indicator, and their expression can tell us about psychological states. However, there are questions about the longer-term consequences if animals express stereotypies: do the stereotypies help in coping? During the prenatal period, stereotypic behavior expressed by the mother can change the phenotype of the offspring, especially regarding emotionality, one mechanism acting via methylation in the limbic system in the brain. Are individuals that show stereotypies for shorter or longer periods all better adjusted, and hence have better welfare, or is the later welfare of some worse than that of individuals that do not show the behavior? Abstract Stereotypies comprise a wide range of repeated and apparently functionless behaviors that develop in individuals whose neural condition or environment results in poor welfare. While stereotypies are an indicator of poor welfare at the time of occurrence, they may have various consequences. Environmental enrichment modifies causal factors and reduces the occurrence of stereotypies, providing evidence that stereotypies are an indicator of poor welfare. However, stereotypy occurrence and consequences change over time. Furthermore, there are complex direct and epigenetic effects when mother mammals that are kept in negative conditions do or do not show stereotypies. It is proposed that, when trying to deal with challenging situations, stereotypies might initially help animals to cope. After further time in the conditions, the performance of the stereotypy may impair brain function and change brain connections, neurophysiology and eventually neuroanatomy. It is possible that reported neuroanatomical changes are an effect of the stereotypy rather than a cause.
1 citations
Dissertation•
01 May 2013
TL;DR: Analysis of the roles of three vegetative profilin members in plant cell and organ development found that defects in each of the three variants gave rise to specific developmental deficiencies, and evidence is presented that mixtures of independent function, quantitative genetic effects, and functional redundancy have preserved the three Vegetative Profilin genes.
Abstract: The actin cytoskeleton is involved in an array of integral structural and developmental processes throughout the cell. One of actin’s best studied binding partners is the small ubiquitously expressed protein, profilin. Arabidopsis thaliana is known to encode a family of five profilin sequence variants: three vegetative profilins that are expressed in all vegetative tissues and ovules, and two that are specifically expressed in pollen. This paper analyzes the roles of three vegetative profilin members, PRF1, PRF2, and PRF3, in plant cell and organ development. Using a collection of knockout or severe knockdown T-DNA single mutants, we found that defects in each of the three variants gave rise to specific developmental deficiencies. Plants lacking PRF1 or PRF2 had defects in rosette leaf morphology and inflorescence stature, while those lacking PRF3 led to plants with slightly elongated petioles. To further examine these effects, double mutants and multiple gene silenced RNAi epialleles were created. These plants displayed significantly compounded developmental defects, as well as novel lateral root growth morphological phenotypes. Microscopic examination of dwarfed plants lacking in profilin variants indicated that they have smaller cells defective in cell elongation. Evidence is presented that mixtures of independent function, quantitative genetic effects, and functional redundancy have preserved the three vegetative profilin genes. We conclude with discussing a model for profilin’s role in cell elongation based upon overall profilin concentrations in the cell.
1 citations
04 Jul 2014
TL;DR: It is suggested that lncRNAs are important to modulate diverse central nervous system processes and are the major factor that is important to the brain development, which may be employed to develop novel diagnostic and therapeutic strategies to treat brain related diseases.
Abstract: Regulatory long non-coding RNAs have been emerged as a major contribution of cognitive evolution in mammalian central nervous system and brain tissues. Though proteins have relatively conserved during evolution, the lncRNAs have evolved rapidly to cope with essential and widespread cellular regulation, partly by directing generic protein function. Long non-coding RNAs, highly yet specifically expressed in mammalian brain, provide tissue- and neuronal activity-specific epigenetic and transcriptional regulation. lncRNAs have been documented to be essential for brain development and be involved in brain related diseases. We suggest that lncRNAs are important to modulate diverse central nervous system processes and are the major factor that is important to the brain development, which may be employed to develop novel diagnostic and therapeutic strategies to treat brain related diseases. Moreover, animal models with altered lncRNA expressions and high-throughput approaches would help to understand the mechanisms of lncRNAs in brain development and the etiology of lncRNA-driven human neurological diseases.
1 citations
Cites background from "Epigenetic codes in cognition and b..."
...The amazing cognitive and behavioral functions in brain may involve in neural networks comprised by billions of neurons (Graff and Mansuy, 2008)....
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10 Mar 2019
TL;DR: In this paper, the authors proposed a framework to improve the quality of the information provided by the Internet for the purpose of improving the health of the Internet and its users, such as health and safety.
Abstract: کچ هدي شيپ هنيمز و فده : لولس اه ي NG2 هب ناونع پ ی زاس ش لولس اه ي لا ی سوردندوگ ی اراد و هدوب ت ي نورون هدننک تظافح شقن ی م ی رضاح هعلاطم زا فده .دنشاب سررب ی اقم و ی هس ثأت ی ر رمت هتفه راهچ ی تخا ن ی را ي لومعم ی پ و ی چ ی حوطس رب هد NG2 زغم تر اه ي و داژن ملاس رن ی .دوب راتس شور و داوم راک : 30 رس و داژن تر ی زا سپ غلاب راتس ی انشآ هتفه ک یی حم اب ی امزآ ط ی هاگش هب تروص فداصت ی رمت هورگ هس هب ی تخا ن ی را ي ور ي س راود خرچ ،هدا رمت ی تخا ن ی را ي ور ي پ راود خرچ ی چ ی لرتنک هورگ و هد میسقت يدنب .دندش هورگ اه ي رمت ی ن ی هتفه راهچ تدم هب هب روط تخا ی را ي لاعف ماجنا هب ی دنتخادرپ ت . شور زا لاا ی ارب از ي هزادنا يریگ NG2 درگ هدافتسا زغم ی سررب .د ی م توافت ی گنا ی ن لحت شور اب اه ی راو ل ی سنا ی ک هفرط قعت نومزآ و ی ب ی کوت ی زا هدافتسا اب ، مرن فا راز SPSS هخسن 20 .تفرگ تروص هتفاي اه رمت ماجنا : ی تخا تان ی را ي ور ي ) هداس راود خرچ P=0/03 ور و ( ي پ راود خرچ ی چ ی هد ) P=0/001 غت ( یی نعم ر ی راد ي حوطس رد NG2 تر زغم اه ي داژن ملاس و ی نچمه .تشاد راتس ی ب ن ی رمت عون ود ن ی نعم توافت ن ی راد ي ) دشن هدهاشم P=0/05 .( هجيتن و ثحب :يريگ اتن ساسا رب ی ج هب تسد هدمآ رمت هتفه راهچ ، ی تخا ن ی را ي پ راود خرچ لدم ود رد ی چ ی لومعم و هد ی ازفا ی نعم ش ی راد ي د حوطس ر NG2 زغم تر اه ي و داژن ملاس رن ی ا راتس ی .درک داج تنرد ی هج ا زا ی رمت شور ود ن ی ن ی تهج ، ثأت ی راذگر ي ور رب تبثم ي ازفا ی ش تیسوردندوگیلا اه تر رد اه ي م ملاس ی ت ناو رمت شور و درک هدافتسا ی تخا ن ی را ي پ ی چ ی شخبرثا هد ی ب ی رتش ي .دراد هژاوديلک :اه رمت ی تخا ن ی را ي لومعم راود خرچ ، ی پ راود خرچ ، ی چ ی ،هد NG2
1 citations
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...European Neuropsychopharmacology 2010;20(1):1-...
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References
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TL;DR: The best understood form of long-term potentiation is induced by the activation of the N-methyl-d-aspartate receptor complex, which allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and post Synaptic mechanisms to generate a persistent increase in synaptic strength.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
11,123 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...These forms f plasticity reflect respectively, an increase and a decrease in he efficiency of synaptic transmission, and have been extenively studied in the hippocampus, a brain area required for earning and memory (for a review see [30])....
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TL;DR: The surface of nucleosomes is studded with a multiplicity of modifications that can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA.
10,046 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...Chronic xposure to an aggressor results in pronounced social avoidnce, prolonged downregulation of two splice variants of Bdnf, dnfIII and BdnfIV in the hippocampus and increased promoter imethylation of H3K27 [102], a mark of transcriptional represion [20]....
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TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
Abstract: Chromatin, the physiological template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-associated proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a “histone code” that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
9,309 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...These nzymes operate both independently and in synergy to establish “histone code”, a highly dynamic and flexible chromatin markng that, in combination with chromatin-associated proteins, etermines the pattern of gene expression in response to given xternal stimuli [24,25]....
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TL;DR: The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development.
Abstract: The character of a cell is defined by its constituent proteins, which are the result of specific patterns of gene expression. Crucial determinants of gene expression patterns are DNA-binding transcription factors that choose genes for transcriptional activation or repression by recognizing the sequence of DNA bases in their promoter regions. Interaction of these factors with their cognate sequences triggers a chain of events, often involving changes in the structure of chromatin, that leads to the assembly of an active transcription complex (e.g., Cosma et al. 1999). But the types of transcription factors present in a cell are not alone sufficient to define its spectrum of gene activity, as the transcriptional potential of a genome can become restricted in a stable manner during development. The constraints imposed by developmental history probably account for the very low efficiency of cloning animals from the nuclei of differentiated cells (Rideout et al. 2001; Wakayama and Yanagimachi 2001). A “transcription factors only” model would predict that the gene expression pattern of a differentiated nucleus would be completely reversible upon exposure to a new spectrum of factors. Although many aspects of expression can be reprogrammed in this way (Gurdon 1999), some marks of differentiation are evidently so stable that immersion in an alien cytoplasm cannot erase the memory. The genomic sequence of a differentiated cell is thought to be identical in most cases to that of the zygote from which it is descended (mammalian B and T cells being an obvious exception). This means that the marks of developmental history are unlikely to be caused by widespread somatic mutation. Processes less irrevocable than mutation fall under the umbrella term “epigenetic” mechanisms. A current definition of epigenetics is: “The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (Russo et al. 1996). There are two epigenetic systems that affect animal development and fulfill the criterion of heritability: DNA methylation and the Polycomb-trithorax group (Pc-G/trx) protein complexes. (Histone modification has some attributes of an epigenetic process, but the issue of heritability has yet to be resolved.) This review concerns DNA methylation, focusing on the generation, inheritance, and biological significance of genomic methylation patterns in the development of mammals. Data will be discussed favoring the notion that DNA methylation may only affect genes that are already silenced by other mechanisms in the embryo. Embryonic transcription, on the other hand, may cause the exclusion of the DNA methylation machinery. The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development. Indeed, the possibility will be discussed that DNA methylation and Pc-G/trx may represent alternative systems of epigenetic memory that have been interchanged over evolutionary time. Animal DNA methylation has been the subject of several recent reviews (Bird and Wolffe 1999; Bestor 2000; Hsieh 2000; Costello and Plass 2001; Jones and Takai 2001). For recent reviews of plant and fungal DNA methylation, see Finnegan et al. (2000), Martienssen and Colot (2001), and Matzke et al. (2001).
6,691 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...ecause of the covalent nature of the binding of methyl groups o the C5 carbon in cytosine, DNA methylation is thought to be he most stable epigenetic mark [9]....
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...DNA methylation is commonly associated with ranscriptional silencing because it can directly inhibit the bindng of transcription factors or regulators, or indirectly recruit ethyl-CpG binding proteins (MBPs), which have repressive hromatin-remodeling functions [9,10]....
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...Most cases of RS are caused by mutaions in the gene coding for methyl-CpG binding protein 2 MeCP2) [62], a member of the MBP family involved in ong-term gene silencing (for a review see [9])....
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TL;DR: Advances in the understanding of the mechanism and role of DNA methylation in biological processes are reviewed, showing that epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression.
Abstract: Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.
5,760 citations
"Epigenetic codes in cognition and b..." refers background in this paper
...ot be explained by changes in the DNA sequence itself [3] reviewed in [4,5])....
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