̽��ֱ�� of Cambridge - Markus Ralser

Could the food we eat affect our genes? Study in yeast suggests this may be the case

cjb250 — Thu, 11 Feb 2016 00:00:32 +0000

̽��ֱ��behaviour of our cells is determined by a combination of the activity of its genes and the chemical reactions needed to maintain the cells, known as metabolism. Metabolism works in two directions: the breakdown of molecules to provide energy for the body and the production of all compounds needed by the cells.

Knowing the genome – the complete DNA ‘blueprint’ of an organism – can provide a substantial amount of information about how a particular organism will look. However, this does not give the complete picture: genes can be regulated by other genes or regions of DNA, or by ‘epigenetic’ modifiers – small molecules attached to the DNA that act like switches to turn genes on and off.

Previous studies have suggested that another player in gene regulation may exist: the metabolic network – the biochemical reactions that occur within an organism. These reactions mainly depend on the nutrients a cell has available – the sugars, amino acids, fatty acids and vitamins that are derived from the food we eat.

To examine the scale at which this happens, an international team of researchers, led by Dr Markus Ralser at the ̽��ֱ�� of Cambridge and the Francis Crick Institute, London, addressed the role of metabolism in the most basic functionality of a cell. They did so using yeast cells. Yeast is an ideal model organism for large scale experiments at it is much simpler to manipulate than animal models, yet many of its important genes and fundamental cellular mechanisms are the same as or very similar to those in animals and humans.

̽��ֱ��researchers manipulated the levels of important metabolites – the products of metabolic reactions – in the yeast cells and examined how this affected the behaviour of the genes and the molecules they produced. Almost nine out of ten genes and their products were affected by changes in cellular metabolism.

“Cellular metabolism plays a far more dynamic role in the cells than we previously thought,” explains Dr Ralser. “Nearly all of a cell’s genes are influenced by changes to the nutrients they have access to. In fact, in many cases the effects were so strong, that changing a cell’s metabolic profile could make some of its genes behave in a completely different manner.

“ ̽��ֱ��classical view is that genes control how nutrients are broken down into important molecules, but we’ve shown that the opposite is true, too: how the nutrients break down affects how our genes behave.”

̽��ֱ��researchers believe that the findings may have wide-ranging implications, including on how we respond to certain drugs. In cancers, for example, tumour cells develop multiple genetic mutations, which change the metabolic network within the cells. This in turn could affect the behaviour of the genes and may explain with some drugs fail to work for some individuals.

“Another important aspect of our findings is a practical one for scientists,” explains says Dr Ralser. “Biological experiments are often not reproducible between laboratories and we often blame sloppy researchers for that. It appears however, that small metabolic differences can change the outcomes of the experiments. We need to establish new laboratory procedures that control better for differences in metabolism. This will help us to design better and more reliable experiments.”

Reference
Alam, MT et al. ̽��ֱ��metabolic background is a global player in Saccharomyces gene expression epistasis. Nature Microbiology; 1 Feb. DOI: 10.1038/nmicrobiol.2015.30

Almost all of our genes may be influenced by the food we eat, according to new research published in the journal Nature Microbiology. ̽��ֱ��study, carried out in yeast – which can be used to model some of the body’s fundamental processes – shows that while the activity of our genes influences our metabolism, the opposite is also true and the nutrients available to cells influence our genes.

In many cases the effects were so strong, that changing a cell’s metabolic profile could make some of its genes behave in a completely different manner

Markus Ralser

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Fruits & Vegetables

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Social yeast cells prefer to work with close relatives to make our beer, bread & wine

Anonymous — Mon, 26 Oct 2015 13:05:30 +0000

̽��ֱ��findings, published today in the open access journal eLife, could lead to new biotechnological production systems based on metabolic cooperation. They could also be used to inhibit cell growth by blocking the exchange of metabolites between cells. This could be a new strategy to combat fungal pathogens or tumour cells.

“ ̽��ֱ��cell-cell cooperation we uncovered plays a significant role in allowing yeast to help us to produce our food, beer and wine,” says first author Kate Campbell.

“It may also be crucial for all eukaryotic life, including animals, plants and fungi.”

Yeast metabolism has been exploited for thousands of years by mankind for brewing and baking. Yeast metabolizes sugar and secretes a wide array of small molecules during their life cycle, from alcohols and carbon dioxide to antioxidants and amino acids. Although much research has shown yeast to be a robust metabolic work-horse, only more recently has it become clear that these single-cellular organisms assemble in communities, in which individual cells may play a specialised function.

For the new study funded by the Wellcome Trust and European Research Council, researchers at the ̽��ֱ�� of Cambridge and the Francis Crick Institute found cells to be highly efficient at exchanging some of their essential building blocks (amino acids and nucleobases, such as the A, T, G and C constituents of DNA) in what they call metabolic cooperation. However, they do not do so with every kind of yeast cell: they share nutrients with cells descendant from the same ancestor, but not with other cells from the same species when they originate from another community.

Using a synthetic biology approach, the team led by Dr Markus Ralser at the Department of Biochemistry started with a metabolically competent yeast mother cell, genetically manipulated so that its daughters progressively loose essential metabolic genes. They used it to grow a heterogeneous population of yeast with multiple generations, in which individual cells are deficient for various nutrients.

Campbell then tested whether cells lacking a metabolic gene can survive by sharing nutrients with their family members. When living within their community setting, these cells could continue to grow and survive. This meant that cells were being kept alive by neighbouring cells, which still had their metabolic activity intact, providing them with a much needed nutrient supply. Eventually, the colony established a composition where the majority of cells did help each other out. When cells of the same species but derived from another community were introduced, social interactions did not establish and the foreign cells died from starvation.

When the successful community was compared to other yeast strains, which had no metabolic deficiencies, the researchers found no pronounced differences in how both communities grew and produced biomass. This is implies that sharing was so efficient that any disadvantage was cancelled out.

̽��ֱ��implications of these results may therefore be substantial for industries in which yeast are used to produce biomolecules of interest. This includes biofuels, vaccines and food supplements. ̽��ֱ��research might also help to develop therapeutic strategies against pathogenic fungi, such as the yeast Candida albicans, which form cooperative communities to overcome our immune system.

Reference

Kate Campbell, Jakob Vowinckel, Michael Muelleder, Silke Malmsheimer, Nicola Lawrence, Enrica Calvani, Leonor Miller-Fleming, Mohammad T. Alam, Stefan Christen, Markus A. Keller, and Markus Ralser

Self-establishing communities enable cooperative metabolite exchange in a eukaryote eLife 2015, https://dx.doi.org/10.7554/eLife.09943

Baker’s yeast cells living together in communities help feed each other, but leave incomers from the same species to die from starvation, according to new research from the ̽��ֱ�� of Cambridge.

̽��ֱ��cell-cell cooperation we uncovered plays a significant role in allowing yeast to help us to produce our food, beer and wine

Kate Campbell

Metabolic cooperation in a social Baker’s yeast community. Pictured is a two-day old yeast community that grows as a colony. Different colours indicate cells producing and consuming different metabolites and nutrients.

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Metabolism may have started in our early oceans before the origin of life

cjb250 — Fri, 25 Apr 2014 15:12:59 +0000

In a study funded by the Wellcome Trust and the European Research Council researchers at the ̽��ֱ�� of Cambridge reconstructed the chemical make-up of the Earth’s earliest ocean in the laboratory. ̽��ֱ��team found the spontaneous occurrence of reaction sequences which in modern organisms enable the formation of molecules essential for the synthesis of metabolites. These organic molecules, such as amino acids, nucleic acids and lipids, are critical for the cellular metabolism seen in all living organisms

̽��ֱ��detection of one of the metabolites, ribose 5-phosphate, in the reaction mixtures is particularly noteworthy, as RNA precursors like this could in theory give rise to RNA molecules that encode information, catalyze chemical reactions and replicate.

It was previously assumed that the complex metabolic reaction sequences, known as metabolic pathways, which occur in modern cells, were only possible due to the presence of enzymes. Enzymes are highly complex molecular machines that are thought to have come into existence during the evolution of modern organisms. However, the team’s reconstruction reveals that metabolism-like reactions could have occurred naturally in our early oceans, before the first organisms evolved.

Life on Earth began during the Archean geological eon almost 4 billion years ago in iron-rich oceans that dominated the surface of the planet. This was an oxygen-free world, pre-dating photosynthesis, when the redox state of iron was different and much more soluble to act as potential catalysts. In these oceans, iron, other metals and phosphate facilitated a series of reactions which resemble the core of cellular metabolism occurring in the absence of enzymes.

̽��ֱ��findings suggest that metabolism predates the origin of life and evolved through the chemical conditions that prevailed in the worlds earliest oceans.

“Our results show that reaction sequences that resemble two essential reaction cascades of metabolism, glycolysis and the pentose-phosphate pathways, could have occurred spontaneously in the earth’s ancient oceans,” says Dr Markus Ralser from the Department of Biochemistry at the ̽��ֱ�� of Cambridge and the National Institute for Medical Research, who led the study.

“In our reconstructed version of the ancient Archean ocean, these metabolic reactions were particularly sensitive to the presence of ferrous iron which was abundant in the early oceans, and accelerated many of the chemical reactions that we observe. We were surprised by how specific these reactions were,” he added.

̽��ֱ��conditions of the Archean ocean were reconstructed based on the composition of various early sediments described in the scientific literature which identify soluble forms of iron as one of the most frequent molecules present in these oceans.

Alexandra Turchyn from the Department of Earth Sciences at the ̽��ֱ�� of Cambridge, one of the co-authors of the study said: “We are quite certain that the earliest oceans contained no oxygen, and so any iron present would have been soluble in these oxygen-devoid oceans. It’s therefore possible that concentrations of iron could have been quite high”.

̽��ֱ��different metabolites were incubated at temperatures of 50-90˚C, similar to what might be expected close to the hydrothermal vents of an oceanic volcano. These temperatures would not support the activity of conventional protein enzymes. ̽��ֱ��chemical products were separated and analyzed by liquid chromatography tandem mass spectrometry.

Some of the observed reactions could also take place in water but were accelerated by the presence of metals that served as catalysts. “In the presence of iron and other compounds found in the oceanic sediments, we observed 29 metabolism-like chemical reactions, including those that produce some of the essential chemicals of metabolism, for example precursors to the building blocks of proteins or RNA,” says Dr Ralser.

“These results indicate that the basic architecture of the modern metabolic network could have originated from the chemical and physical constraints that existed on Earth billions of years ago.”

Copy adapted from an original press release from the Wellcome Trust.

Reference
Keller et al. (2014) Mol Syst Biol 10:725. Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean

̽��ֱ��chemical reactions behind metabolism – the processes that occur within all living organisms in order to sustain life – may have formed spontaneously in the Earth’s early oceans, according to research published today.

̽��ֱ��basic architecture of the modern metabolic network could have originated from the chemical and physical constraints that existed on Earth billions of years ago

Markus Ralser

Dhilung Kirat

After storm

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