Lysine methylation has been traditionally associated with histones and epigenetics. Recently, lysine methyltransferases and demethylases – which are involved in methylation of non‐histone substrates – have been frequently found deregulated in human tumours. In this realm, a new discovery has unveiled the methyltransferase SMYD3 as an enhancer of Ras‐driven cancer. SMYD3 is up‐regulated in different types of tumours. SMYD3‐mediated methylation of MAP3K2 increases mutant K‐Ras‐induced activation of ERK1/2. Methylation of MAP3K2 prevents it from binding to the (...) phosphatase PP2A, thereby impeding the impact of this negative regulator on Ras‐ERK1/2 signals, leading to the formation of lung and pancreatic adenocarcinomas. Furthermore, depletion of SMYD3 synergises with a MEK inhibitor, currently in clinical trials, to block Ras‐driven pancreatic neoplasia. These results underscore the importance of lysine methylation in the regulation of signalling pathways relevant for tumourigenesis and endorse the development of drugs targeting unregulated lysine methylation as therapeutic agents in the struggle against cancer. (shrink)

The existence of DNA methylation in insects has been a controversial subject over a long period of time. The recently completed genome sequence of the honeybee Apis mellifera has revealed the first insect with a full complement of DNA methyltransferases.1 A parallel study demonstrated that these enzymes are catalytically active and that Apis genes can be methylated in specific patterns.2 These findings establish bees as a model to analyze the function of DNA methylation systems in invertebrate organisms and (...) might also be important to understand evolutionary aspects of DNA methylation in higher eukaryotes. BioEssays 29: 208–211, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

A recurrent theme in eukaryotic genome regulation stipulates that the properties of DNA are strongly influenced by the nucleoprotein complex into which it is assembled. Methylation of cytosine residues in vertebrate genomes has been implicated in influencing the assembly of locally repressive chromatin architecture. Current models suggest that covalent modification of DNA results in heritable, long‐term transcriptional silencing. In October of 2003, two manuscripts1,2 were published that challenge important aspects of this model, suggesting that modulation of both DNA (...) class='Hi'>methylation itself, as well as the machinery implicated in its interpretation, are involved in acute gene regulation. BioEssays 26:217–220, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Primary and methyl aliphatic halides and tosylates undergo substitution reactions with nucleophiles in one step by the classic S N 2 mechanism, which is characterized by second-order kinetics and inversion of configuration at the reaction center. Tertiary aliphatic halides and tosylates undergo substitution reactions with nucleophiles in two (or more) steps by the classic S N 1 mechanism, which is characterized by first-order kinetics and incomplete inversion of configuration at the reaction center due to the presence of ion pairs. When (...) the nucleophile is also the solvent, the substitution reaction is called a solvolysis, and both the S N 2 and S N 1 reactions now obey first-order kinetics. Schleyer and Bentley have provided solid, but not conclusive, evidence that secondary substrates undergo solvolysis by a merged mechanism, one that blends characteristics of both the S N 2 and S N 1 mechanisms. The following paper presents the history of their sustained pursuit of a merged mechanism and subsequent rebuttals to this claim. Several issues related to the philosophy and sociology of science are also discussed. (shrink)

Methyl CpG binding protein 2 (MeCP2) was initially isolated as an exclusive reader of DNA methylated at CpG. This recognition site, was subsequently extended to other DNA methylated residues and it has been the persisting dogma that binding to methylated DNA constitutes its physiologically relevant role. As we review here, two very recent papers fundamentally change our understanding of the interactions of this protein with chromatin, as well as its functional attributes. In the first one, the protein has been shown (...) to bind to tri‐methylated histone H3 (H3K27me3), providing a hint for what might turn out to be the first described chromodomain‐containing protein reader in the animal kingdom, and unequivocally demonstrates the ability of MeCP2 to bind to nonmethylated CpG regions of the genome. The second paper reports how the protein dynamically participates in the formation of constitutive heterochromatin condensates. Histone H3K27me3 is a critical component of this form of chromatin. (shrink)

Parental effects are a major source of phenotypic plasticity and may influence offspring phenotype in concert with environmental demands. Studies of “environmental epigenetics” suggest that (1) DNA methylation states are variable and that both demethylation and remethylation occur in post‐mitotic cells, and (2) that remodeling of DNA methylation can occur in response to environmentally driven intracellular signaling pathways. Studies of mother‐offspring interactions in rodents suggest that parental signals influence the DNA methylation, leading to stable changes in gene (...) expression. If parental effects do indeed enhance the “match” between prevailing environmental demands and offspring phenotype, then the potential for variation in environmental conditions over time would suggest a mechanism that requires active maintenance across generations through parental signaling. We suggest that parental regulation of DNA methylation states is thus an ideal candidate mechanism for parental effects on phenotypic variation. (shrink)

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and function. The latter point is (...) of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

Flavin‐containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo‐2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo‐2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S‐adenosyl‐methionine (SAM) to S‐adenosyl‐homocysteine (SAH), consequently diminishing methylation capacity. Here we (...) discuss how FMO‐2‐mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo‐2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan. (shrink)

Expression and transposition of the Suppressor‐mutator (Spm) transposon of maize are controlled by interacting epigenetic and autoregulatory mechanisms. Methylation of critical element sequences prevents both transcription and transposition, heritably inactivating the element. The promoter, comprising the terminal 0.2 kb of the element, and a 0.35‐kb, highly GC‐rich, downstream sequence are the methylation target sequences. The element encodes two proteins necessary for transposition, TnpA and TnpD. There are multiple TnpA binding sites, both in the 5′ terminal promoter region and (...) at the element's 3′ end. In addition to its role in transposition, TnpA is both a positive and a negative regulator of transcription. TnpA represses the element's promoter when it is not methylated. When the element is inactive and its promoter methylated, TnpA activates the methylated promoter and facilitates both its transient and heritable demethylation. (shrink)

This paper reviews a theory on the physiological conditions of consciousness. The theory consists of four hypotheses: (1) The occurrence of states of consciousness depends on the formation of higher-order representations that represent the internal state of the brain itself. (2) Higher-order representations are instantiated by the spatio-temporal activity pattern of large-scale neuronal assemblies. (3) The N-methyl-D-aspartate (NMDA) synapse plays a crucial role in the generation of conscious states by implementing the binding mechanism that the brain uses to produce large-scale (...) assemblies. (4) The activation state of the NMDA receptor determines the rate at which representational structures can be built up. Unconsciousness or altered states of consciousness occur if, and only if, NMDA-dependent binding processes are inhibited. (shrink)