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Di Cerbo V.,Max Planck Institute of Immunobiology and Epigenetics | Schneider R.,LMU
Briefings in Functional Genomics | Year: 2013

Lysine N-ε-acetylation is a post-translationalmodification that regulates the function of histone and non-histone proteins. In several malignancies, histone acetyltransferase (HAT) activities are disturbed as a consequence of various genetic or epigenetic alterations. In particular, HATs can function as tumor suppressors, helping cells control cellular proliferation and cell cycle, and also as oncogenes, because abnormal acetylation can activate malignant proteins and contribute to cancer. An impaired acetylation profile can be indicative of a pathological process, and thus evaluation of histone acetylation could be used as a predictive index of patient survival or therapy outcome. Therefore, epigenetic therapy might be a very effective strategy to defeat cancer.With the use of histone deacetylase inhibitors and acetylation modulators (e.g. HAT inhibitors, bromodomain inhibitors), we are paving the way for a future epigenetic drug control of human diseases ©The Author 2013. Published by Oxford University Press. All rights reserved. Source

Fritzsch H.,LMU
Progress in Particle and Nuclear Physics | Year: 2011

We discuss the fundamental constants of physics within the Standard Model of particle physics. In this model there are 28 fundamental constants, e.g. the constant of gravity or the fine-structure constant. We consider possible changes of these constants on the cosmological time scale. © 2011 Published by Elsevier B.V. Source

From cereals to trees: More than 80% of land plants form symbioses with arbuscular mycorrhizal fungi. The fungi colonize the roots, and provide their host with inorganic nutrients – primarily phosphate – which are otherwise poorly accessible to plants. In return, the plants provide their fungal guests with energy-rich carbohydrates. This type of symbiosis evolved more than 400 million years ago and is indispensable for the viability of many plant species. To enable the fungi to supply the host with nutrients, their hyphal threads must first enter into the root, in which they form branched tree-like structures known as arbuscules (from the Latin arbuscula = a shrub). The arbuscules then release the minerals, which the fungus has taken up from the surrounding soil, to the plant. "The successful formation of such alien structures inside plant cells demands a fundamental reconfiguration of the metabolism of the root cells and must be tightly regulated by the plant", explains LMU biologist Caroline Gutjahr. Together with the members of her research group, Gutjahr recently identified one of the crucial elements in this process. The findings have now appeared in the journal Current Biology. Perhaps not surprisingly, the degree of colonization of roots by the fungi depends on the physiological status of the plant, including the level of its actual requirement for the nutrients supplied by the symbionts. Thus, if the plant already has access to an adequate supply of phosphate, formation of arbuscules is actively inhibited. "However, up until now, no molecular mechanism was known that might be capable of controlling the extent of arbuscule formation in accordance with the plant's physiological needs," Gutjahr says. In order to pinpoint mechanisms used by the host to control arbuscule formation, the researchers focused on a mutant strain of the plant Lotus japonicus (a species of legume, related to beans, peas and lentils), in which the process is perturbed. "In this strain, we identified the gene affected by the mutation as RAM1, the product of which is required for the activation of other genes, and hence for the production of the proteins they encode", says Gutjahr. "These proteins, in turn, are very probably required to permit arbuscule formation to proceed. Their precise functions remain to be characterized in upcoming projects." The RAM1 gene itself is strongly activated during arbuscule formation, so the mechanisms responsible for its own activation are of great interest. Gutjahr and her colleagues have now shown that two different regulatory proteins are required to induce the gene. The first is the transcription factor CYCLOPS, which was already known to play a key role in the regulation of root symbioses. The second protein, called DELLA, was also familiar, albeit in another context. DELLA forms part of a signal transduction pathway that is activated by the plant hormones called gibberellins, which are essential for the control of the plant physiology and growth. "To our surprise, we found that, in the context of RAM1 activation, CYCLOPS and DELLA interact with one another directly," says Priya Pimprikar, a doctoral student in Gutjahr's group and first author on the new study. "With this interaction, we believe we have identified, for the first time, one of the central nodes upon which information relating to symbiosis on the one hand, and plant physiology on the other, converges, thus enabling the plant to determine the extent of root colonization in accordance with its current need for phosphate, for instance", says Gutjahr. Reducing the need for scarce resources The symbiosis between plants and mycorrhizal fungi is also of considerable economic and ecological significance, as intensive farming requires huge inputs of artificial fertilizer each year to maintain the fertility of the soil. These fertilizers contain mineral phosphates which are only available in finite quantities, and some estimates suggest that reserves of these compounds may run out within the next 100 years. "Arbuscular mycorrhiza can help reduce the need for the application of phosphates in agriculture," Gutjahr points out. "And a better understanding of the mechanisms underlying arbuscule formation is an important prerequisite for the success of plant breeding efforts to enhance the efficiency of this type of symbiosis." More information: Priya Pimprikar et al. A CCaMK-CYCLOPS-DELLA Complex Activates Transcription of RAM1 to Regulate Arbuscule Branching, Current Biology (2016). DOI: 10.1016/j.cub.2016.01.069

News Article
Site: http://phys.org/chemistry-news/

The earliest phase in the process that gave rise to living organisms on our planet is thought to have involved selective interactions between simple prebiotic molecules that enabled them to form progressively more complex chemical structures. These metastable structures eventually became capable of storing genetic information and transmitting it by self-replication. The most likely candidates for such self-replicating systems are polymeric molecules made up of subunits called ribonucleotides. These RNA molecules in turn could have provided the starting point for biological evolution, which led to the first cell and everything that followed. Christof Mast and Dieter Braun (Professor of Systems Biophysics at LMU) have been exploring how precursor molecules such as ribonucleotides (and the deoxyribonucleotides of the hereditary material DNA) present in Earth's primordial ocean could have accumulated locally in concentrations high enough to permit them to interact. But how was the wheat separated from the chaff in such systems? In other words, what mechanism could have separated 'useful' from 'useless' RNA molecules, and concentrated the former sufficiently to give them a chance to interact with other RNA chains and be elongated? New work by Braun, who is also a member of the Nanosystems Initiative Munich (NIM) and the Center for NanoScience (CeNS), together with Christof Mast and Matthias Morasch, points to a possible answer. In earlier laboratory experiments, Braun and his colleagues have shown that temperature differences in tiny water-filled channels, such as those found at hydrothermal vents and in the igneous rock extruded at mid-ocean ridges, are able to partition DNA molecules based on their lengths. Now they demonstrate that the same mechanism can also sort DNA strands that differ in their nucleotide sequences from each other. Their findings appear in the latest issue of the journal Angewandte Chemie. Instead of samples of porous rock, the LMU researchers used glass capillary tubes filled with an aqueous solution containing mixtures of two DNA fragments with slightly different nucleotide sequences for their experiments. "DNA is chemically closely related to RNA and behaves in a similar way under our experimental conditions. But it is more stable and therefore easier to handle," says Matthias Morasch, first author of the new study. The DNA-containing glass "pores" were then heated from one side, generating a gradient of approximately 17°C within the capillary, and the distribution of the DNA molecules was analyzed. Under these conditions, the different DNA molecules were found to separate into homogeneous, highly concentrated assemblies, depending on their sequences and their ability to interact with each other via complementary base-pairing. Thus in addition to sorting molecules according to their lengths, temperature differences can also drive sequence-dependent sorting. Both effects are based on the phenomenon of thermophoresis, the differential response of components of molecular mixtures to temperature gradients. "The separation is so effective that certain types of fragments actually condense into gels when they hybridize with complementary partner molecules.—Even more strikingly, sequences that differ by only a few bases are partitioned into different gels," Mast explains. This degree of specificity was a big surprise, for DNA gels formed by drying show no evidence of sequence-dependent differentiation. This argues that it is the temperature gradient within the pores that makes the crucial difference. "Settings in which pores in volcanic rock were exposed to directional heat flow were probably very common on the young Earth," says Braun. So temperature-driven sorting may well have provided an important mechanism for the partitioning and concentration of biomolecules that could readily interact with each other, thus allowing them to form longer and longer polymer chains—the essential prerequisite for the origin of life. Explore further: Researchers model how migration of DNA molecules is affected by charge, salt species, and salt concentration

News Article
Site: http://phys.org/biology-news/

The aging process is accompanied by characteristic changes in physiology whose overall effect is to decrease the capacity for tissue repair and increase susceptibility to metabolic disease. In particular, the overall level of metabolic activity falls, and errors in the regulation of gene activity become more frequent. Now, a collaborative study by two research groups at LMU's Biomedical Center, led by Axel Imhof (Professor of Molecular Biology) and Andreas Ladurner (Professor of Physiological Chemistry), has shown in the fruitfly Drosophila melanogaster that such age-dependent changes are already detectable in middle age. Genetic investigation of the signal pathways involved in mediating this effect identified a common process—the modification of proteins by the attachment of so-called acetyl groups (CH3COO-) to proteins—that links the age-related changes at the metabolic and genetic levels. Their findings appear in the journal EMBO reports. As we age, the efficiency of the mitochondria progressively declines. Mitochondria are subcellular organelles in the cells of higher organisms that convert nutrients into biochemically usable energy. Mitochondria also possess their own genome, and mutations in this mitochondrial DNA have been linked to a reduction in lifespan. Paradoxically, however, several studies have shown that reducing levels of mitochondrial activity—by restricting food intake, for instance—can actually extend lifespan. "These findings imply that the primary cause of aging cannot simply lie in a reduction in overall metabolic activity, so the whole issue must be more complicated than that," Imhof points out. Most studies of the aging process employ comparisons between young and old individuals belonging to the same species. "However, in aged animals, many of the potentially relevant physiological operations no longer function optimally, which makes it difficult to probe their interactions. That is why we chose to look in Drosophila to see whether we could find any characteristic metabolic changes or other striking modifications in flies on the threshold of old age and, if so, ask how these processes interact with each other," he explains. The two teams first made the surprising discovery that middle-aged male flies (7 weeks old) actually consume more oxygen than their younger conspecifics. This points to a metabolic readjustment which is accompanied by an increase in mitochondrial activity.—And indeed, the researchers noted a rise in the intracellular concentration of acetyl-CoA in these flies. Acetyl-CoA is a metabolite that is produced in the mitochondria, which participates in large number of processes in energy metabolism. Furthermore, it is an important source of acetyl groups for the chemical modification of proteins. "Acetyl groups are attached to specific positions in certain proteins by dedicated enzymes, and can be removed by a separate set of enzymes. These modifications modulate the functions of the proteins to which they are added," Ladurner explains. "And our experiments have shown that many proteins are much more likely to be found in acetylated form in middle-aged flies than in younger individuals." Strikingly, this is true not only for proteins that are involved in basic metabolism, but also for proteins that are directly responsible for regulating gene expression. In the cell nucleus, the genomic DNA molecules are wrapped around "spools" made of proteins called histones. These spools or "nucleosomes" are tightly packed together, and keep the nuclear DNA in a compact, condensed form. Various chemical modifications of the nucleosomal histones—including acetylation—regulate the accessibility of the DNA to the enzymes required for gene expression, and thus determine which genes are active at any given time. "We were able to show that the histones in middle-aged flies are overacetylated," Imhof says. "This reduces the packing density of the DNA, and with it the stringency of gene regulation. The overall result is a rise in the level of errors in the expression of the genetic information, because genetic material that should be maintained in a repressed state can now be reactivated." And Ladurner adds: "In the prime of their lives, fruitflies begin to produce a surfeit of acetylated proteins, which turns out to be too much of a good thing." Taken together, these findings indicate that changes in acetylation may be a key factor in the process of natural aging, reflecting alterations in basic metabolism as well as modifying gene regulation. "A rise in the level of protein acetylation seems to be linked to a decrease in life expectancy," says Ladurner. "For inhibition of an acetylase enzyme which specifically attaches acetyl groups to histones, or attenuation of the rate of synthesis of acetyl-CoA—which reduces the supply of acetyl groups - reverses many of the age-dependent modifications seen in these animals, and both interventions are associated with a longer and more active lifespan." The researchers are now planning to look for comparable effects in mammals. "If that turns out to be the case, then the enzymes that specifically acetylate histones might well be interesting targets for the development of novel therapeutic agents that correct age-dependent dysregulation," says Imhof. "Partial inhibitors that reduce enzyme activity without completely blocking it would probably be most effective in this context." Explore further: New way found by which metabolism is linked to the regulation of DNA More information: S. Peleg et al. Life span extension by targeting a link between metabolism and histone acetylation in Drosophila, EMBO reports (2016). DOI: 10.15252/embr.201541132

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