söndag 11 november 2012

Methyldynamics behind virtually all pathologies?

A remarkable growth in the understanding of epigenetics and the impact of epigenetics on contemporary biology has occurred in recent years. This growth in the field of epigenetics has transformed our conceptualization of the impact of the environment upon our genes and upon our health. The nature and nurture relation is essential for function. Epigenetic modifications shape behavior, modulate stress responsivity, and alter immune function. This facet of epigenetics seeks to understand the interactive linkages that connect the psychological and social environment with the epigenetic processes that modulate gene expression and influence behavior. In a similar manner, the integrative field of psychoneuroimmunology continues to advance the understanding of the complex networks that connect brain, behavior and immunity. Stressors and/or adverse psychosocial environments can affect gene expression by altering the epigenetic patterns. The emphasis on genome itself is no longer particularly important. The dynamic modulations behind gene function are more interesting.

The Human Epigenome Project:  Methylation is the only flexible genomic parameter that can change genome function under exogenous influence. Hence it constitutes the main and so far missing link between genetics, disease and the environment that is widely thought to play a decisive role in the aetiology of virtually all human pathologies.

DNA expression is regulated by acetylation and deacetylation as a compression - expansion of the DNA chromatine. Also epigenetic factors are important for both  1) histone modulation and 2) arginine-lysine changes of DNA expansion (activation) /compression (inhibition), 3) and/or ncRNA expression. Both NO (from arginine) and histone deacetylase activity (HDAC; see next post) regulate gene expressions and the direction of other cellular processes. The biological influences achieved by various histone and DNA modifying enzymes eventually require that histone and DNA be modified in a highly dynamic way. Epigenetic modifications can be modulated by directly inhibiting modifying enzymes or blocking co-factor recruiting pathways, as instance. The best characterized 'erasers' are the histone deacetylases (HDACs). For a review of HDACs see (De Ruijter et al., 2003), but they are found for all categorizations of modulations.

DNA associates with histone proteins to form chromatin. From Wikipedia, epigenetics. A better figure is here.  A ribbon diagram of a nucleosome with central histones, their amino terminal tails, with DNA wrapped about the exterior surface. + short video of the DNA compression.

Epigenetics and Psychoneuroimmunology: Mechanisms and Models Mathews and Janusek 2010

In vertebrates, approximately 2 meters of DNA are contained within each cell and this DNA is packaged into chromatin in a manner that permits transcription of some loci and suppression of other loci. The basic unit of chromatin is the nucleosome, which is comprised of four core histones (H2A, H2B, H3, H4, two of each) around which 146 base pairs of DNA are wrapped.  The core histones are predominantly globular except for their amino terminal “tails,” which are unstructured. A striking feature of histones, and particularly of their tails, is the large number and types of amino acid residues that can be modified. These distinct types of modification include; acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, deimination and proline isomerization (Kouzarides, 2007). Histones modification has been detected at over sixty different amino acid residues, but with extra complexity resulting from methylation at lysine or arginine residues that may be of three forms: mono-, di-, or trimethyl for lysines and mono- or di- (asymmetric or symmetric) for arginine. This vast array of modifications provide for enormous modification of functional responsivity.

The "epigenome" refers to the overall epigenetic state of a cell.  Epigenetic changes are preserved when cells divide, but mostly within one individual organism's lifetime, but, if gene disactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation. This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA, a form of Lamarckism. This was in fact how the inherited epigenetic mechanism was detected by swedish scientists not so long ago. Diabetics and starvation as instance had herited effects, see the Överkalix study with Marcus Pembrey and colleagues.

The "epigenetic code"
could represent the total state of the cell; relevant forms of epigenetic information such as the histone code or direct DNA methylation patterns, or RNA modifications. The way that the cells stay differentiated in the case of DNA methylation is clearer to us than it is in the case of histone shape.

One  thinking is that this tendency of acetylation is associated with "active" transcription as biophysical nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. This is the "cis" model of epigenetic function. There is also a 'trans' function.
Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation, ubiquitylation, phosphorylation and sumoylation. Acetylation is the most highly studied of these modifications.

Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently than acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code

There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
  1. The first way is post translational modification of the amino acids that make up histone proteins, long chains of amino acids, and if they are changed, the shape of the histone sphere might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around it, these modified histones would ensure that a differentiated cell would stay differentiated, and not convert back into being a stem cell.
  2. The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing up with a guanine. However, some areas of the genome are methylated more heavily than others, and highly methylated areas tend to be less transcriptionally active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from this parent (genetic imprinting). Certain enzymes  have a higher affinity for the methylated cytosine, and induce then more methylation. Hypermethylation typically occurs at CpG islands in the promoter region and is associated with gene inactivation. Global hypomethylation has also been implicated
The RNA World, = before gene regulation.
There is an RNA component, possibly involved in epigenetic gene regulation. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.
Other epigenetic changes are mediated by the production of different splice forms of RNA, alternative splicing, see below,  or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are most often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion.

Alternative splicing modulation of the pyruvate kinase M gene involves a choice between mutually exclusive exons 9 and 10, writes Wang et al in Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides, 2012. One alternative is crucial for aerobic glycolysis (the Warburg effect) and tumour growth. Splicing enhancer elements that activate exon 10 are mainly found in exon 10 itself, and deleting or mutating these elements increases the inclusion of exon 9 in cancer cells. The 'antisensing of oligonucleotides'-mediated switch in alternative splicing leads to apoptosis in glioblastoma cell lines, and this is caused by the downregulation of PK-M2,not from another kinase. Note that this are changes in RNA:s only, not genes, so there are a very rich RNA regulating world that we are mostly unaware of yet.

Emotions are strong modulators.
This excerpt links the exon modulations and signalling events in cells induced by motherly care first week after birth.
The exact mechanism whereby maternal LG behavior (L=low) influences methylation of the GR promoter is currently unknown. Yet a series of studies implicate the involvement of the transcription factor, nerve growth factor-inducible protein A (NGFI-A), which functions to transcribe the gene that encodes for GR in the hippocampus. It is proposed that NGFI-A, couples with other transcription factors, cyclic-AMP response element binding protein (CREB) and specific protein 1 (SP-1), to bind to the GR 5’ untranslated promoter exon 17. The binding of this complex of proteins has been theorized to contribute to the reconfiguring of the methylation pattern of GR promoter exon 17. The timing is critical in that this re-configuration of methylation is dependent upon levels of maternal LG during the first postnatal week (Weaver et al., 2004; Weaver et al., 2007). Following birth there is rapid de novo methylation of GR exon 17, which is then demethylated over the course of the first postnatal week. It is this postnatal demethylation that is regulated by maternal LG behavior.
  • Other chapters in this remarcable study: 
  • Epigenetic Perpetuation of Behavior Across Generations 
  • Child Abuse, Suicide, and Epigenetic Modification 
  • Prenatal Depression, Epigenetics and Infant Stress Response 
  • Maternal Separation Stress, AVP, and Epigenetics 
  • Early Life Adversity and Epigenetic Modification of BDNF Expression = Brain derived neurotrophic factor 
  • Stress-Induced Depression Models and Epigenetic Modification of BDNF 
  • Epigenetic Mechanisms in Aging-Associated Memory Impairment 
  • Resilience to Stress-Induced Depression and Epigenetics 
  • Stressor Duration and Epigenetic Modification 
  • Post Traumatic Stress Disorder and Epigenetics 

From the study: It is clear that epigenetic modifications (e.g. those described above) serve as the molecular basis for environmental signals that influence behavioral outcomes and, as such, provide a bridge between the psychosocial world and the biological. This is congruent with psychoneuroimmunology, which seeks to understand the impact of environmental stimuli, especially psychosocial stimuli, on behavior, emotions, neuroendocrine stress responsivity, and immune function. There is no doubt that the genome of an individual provides the blueprint for biological responsivity. However, the epigenome adds another layer ‘on top of the genome’ and serves to modulate gene expression in response to environmental cues. It is likely that the interconnectivity among brain, behavior, and immunity may in fact be directed epigenetically. How, when and where the genetic blueprint will be used in response to a particular stimulus will be a summation of biological networks within the individual. This will include not just DNA recognition events or transcriptional circuits but also the instruction for the use of the blueprint, by epigenetic responsivity that regulates ordered or disordered gene expression patterns. Given the focus of psychoneuroimmunology, epigenetic approaches are particularly appealing and, most importantly, consistent with the concept that brain, behavior and immunity are intimately linked and responsive to environmental context. Intriguing and emerging evidence implicates epigenetic modifications as mediators of psychosocial-biological effects and makes analysis of epigenetics/epigenomics essential to understanding the interconnections among those systems that represent the core of pyschoneuroimmunology. These epigenetic effects have been demonstrated to be related to forms of histone modification, DNA methylation and/or ncRNA expression for a variety of immune based diseases including; systemic lupus erythematosus and rheumatoid arthritis (Martino and Prescott, 2010; Trenkmann et al., 2010) type 1 diabetes, celiac disease and idiopathic thrombocytopenia (Brooks et al., 2010), multiple sclerosis (Lincoln and Cook, 2009), as well as asthma and allergy (Martino and Prescott, 2010; Handel et al., 2010). There have been suggestions that psychosocial distress may contribute to either the exacerbation or development of these diseases. It is therefore plausible that psychosocial distress may impact the immune system by epigenetic processes. Evolving evidence suggests that epigenetic modification may contribute to major psychoses and depression (Feinberg, 2010; Janssen et al., 2010) or obesity (Handel et al., 2010). Not all genes may be responsive or susceptible to epigenetic modification. Much of DNA is inaccessible within a cell and may not be responsive to environmentally induced chromatin remodeling signals (Fraser and Bickmore, 2007). For example, Weaver et al. found that infusion of an HDAC inhibitor into the adult rat hippocampus altered expression of only about 2% of all genes normally expressed (Weaver et al., 2006). It is possible that a relatively restricted pool of adult genes may be dynamically responsive to environmental cues. Certainly, it is unlikely that all genes can be modified through environmentally induced epigenetic processes. Future investigations will be challenged to link epigenetic modifications to functional changes in the expression of specific genes and moreover, to relate these changes to physiological and/or psychological outcomes. It is such linkages that are essential to draw meaningful conclusions as to the biological and health-relevant significance of epigenetic modification. It is unclear whether the evaluations of surrogate epigenetic marks in blood, saliva, and/or buccal swabs reflect such marks in other disease associated tissues. Epigenetic marks are tissue and cell specific, as well as dependent on stage of life and gender. In conclusion, it is likely that epigenetic patterns translate or at least contribute to the relationship between the environment and human health. This possibility opens wide a vista of potential interventions, including behavioral or dietary interventions that can take advantage of the plasticity of the epigenome (Handel et al., 2010).

Drug development has focused mainly on histone acetyltransferase (HAT) and histone deacetylase (HDAC). This is the reason for this short introduction. There are news about memory formation and synaptic plasticity. I wanted to put them in a context.

"Epigenetics, Brain, Behavior, and Immunity" gives a good overview of epigenetics  provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome.

This is something pointed out also by Radoslav Bozov in his paper 'Theory of Carbon Signaling. Negentropy vs Entropy. Emergence of Self Propagated Biological Systems', with whom I have discussed much. See also my earlier posts Life is part of the environment, the molecular mechanisms of innate immunity, cancer not a result of mutations the informational problem - cell membrane and promoter - telomeres and loops. Also thanks to TGD.

7 kommentarer:

  1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218240/ N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO

    http://phys.org/news/2011-10-links-common-rna-modification-obesity.html New research links common RNA modification to obesity

  2. Anyone who has been to the doctor has probably been through a reflex test . What is a reflex? It is a nerve circuit simply responding to outside stimuli by caused a muscle contraction. The most common type of reflex testing in adults is done by hitting the knee with a small rubber hammer. The resulting jerk confirms the health of the lower spinal cord. By testing reflexes in such a matter, doctors can confirm that the spinal cord has not sustained any injuries without turning to more intrusive exams.

    1. What has that to do with methyldynamics? The reflexes doctors test are rude and primitive, of about no value here. Only the principle of a nerve loop is useable.

  3. http://www.scientificamerican.com/article.cfm?id=is-free-radical-theory-of-aging-dead


  4. Targeting DNA methylation for cancer therapy has had a rocky history. The first reports on DNA methylation changes in cancer described global loss of methylation, which has been suggested to drive tumorigenesis through activation of oncogenic proteins or induction of chromosomal instability. In this context, reducing DNA methylation was viewed as a tumor-promoting event rather than a promising cancer therapy. The idea of inhibiting DNA methylation therapeutically emerged from subsequent studies showing that, in parallel to global decreases in methylation, several genes (including many critical to the tumor phenotype) displayed gains of methylation in their promoters during tumorigenesis, a process associated with epigenetic silencing of expression and loss of protein function. This led to revival of interest in drugs discovered decades ago to be potent inhibitors of DNA methyltransferases. These drugs have now been approved for clinical use in the United States in the treatment of myelodysplastic syndrome, thus opening the floodgate for a whole new approach to cancer therapy—epigenetic therapy. http://clincancerres.aacrjournals.org/content/13/6/1634.abstract

    DNA Methylation as a Therapeutic Target in Cancer
    Proposed mechanism of action of DNA methylation inhibitors in cancer therapy. A hypothetical tumor-suppressor gene promoter is shown switching methylation status from unmethylated and expressed in normal tissue to...
    Fig. 1.

    Proposed mechanism of action of DNA methylation inhibitors in cancer therapy. A hypothetical tumor-suppressor gene promoter is shown switching methylation status from unmethylated and expressed in normal tissue to hypermethylated and silenced in cancer tissue. This switch requires the activity of DNA methyltransferases (DNMT), which are also required to maintain the hypermethylated state after each round of DNA replication. Inhibitors of DNA methyltransferases will result in failure to remethylate after DNA replication, which eventually leads to appearance of totally unmethylated alleles that reactivate gene expression. This effect on gene expression is then hypothesized to have pleiotropic effects on cancer cell biology, including induction (or facilitation) of differentiation, apoptosis, senescence, and immune response, for example.

  5. Vast Complexity of Chromatin 3D Shapes

    N6-methyladenosine marks primary microRNAs for processing http://dx.doi.org/10.1038/nature14281

    Our 1996 Hormones and Behavior review linked pre-mRNAs (microRNAs) to RNA-mediated cell type differentiation in species from yeasts to mammals via what was known about the conserved molecular mechanisms of nutrient-dependent RNA-mediated protein folding and the pheromone-controlled physiology of reproduction.

    From Fertilization to Adult Sexual Behavior http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1996-from-fertilization.html

  6. See also:
    Unraveling the secrets of RNA-mediated events http://rna-mediated.com/unraveling-the-secrets-of-rna-mediated-events/