Scientists in Cambridge, UK, using a mouse with a human chromosome in its cells, discovered that gene expression, contrary to what was previously thought, is mostly controlled by regulatory DNA sequences.
Mice and humans (and most vertebrates) share the majority of their genes but a distinct gene regulation – so, when and where these shared genes become activated – assures their many individual characteristics, and knowledge of this regulation is crucial if we want one day to be able to control gene expression.
These new results - just published on the journal Science – challenge current belief that gene regulation is mediated by a combination of many factors, implying that, to be able to understand the mechanisms behind different specialised cells, scientists will have to track species-specific regulatory pieces of DNA, what will be no easy task. The research has implications in the study of phenomena as diverse as genetic diseases, tissue and organ growth and even cloning.
In the last two decades new techniques to study the genome have revealed how genetically similar we are to other vertebrates with humans having more than 99% of gene homology (similarity) with chimps or, even more surprisingly, as much as 85% with mice. Still, we are undoubtedly very different and the explanation relies on different patterns of gene regulation throughout the body, which need to be understood if we want to comprehend (and one day control) how different cells, tissues and organs originate.
In order to investigate how gene regulation is mediated Michael D. Wilson, Nuno L. Barbosa-Morais, Duncan T. Odom (Cancer Research UK and University of Cambridge) and colleagues (London and Minnesota took advantage of an unique mouse called Tc1, which was developed to study Down syndrome (a disease where patients have an extra chromosome 21) and has an extra (human) chromosome 21 in addition to its normal mouse genome.
“What makes this model so extraordinary is that we have an entire chromosome of a species inside the cellular environment of another species, allowing us to find if gene expression is determined by the (human) DNA sequence or by the (mouse) environment” highlights Nuno Barbosa-Morais, a Portuguese researcher and one of the study’s first authors.
To compare gene expression patterns in the human and mouse chromosomes the researchers analysed the behaviour of set of proteins called transcription factors. When a gene is expressed, the first step - called transcription - consists in passing the information on the DNA to a molecule of RNA. Transcription factors - by binding to specific (activator or repressor) sequences of DNA adjacent to the genes they regulate – control which genetic information is transferred to the RNA during transcription, and consequently which genes are expressed. In fact, genes are often surrounded by several binding sites and depending on the combinations of transcription factors binding where, the genes are activated or repressed.
For the experiments in this article Wilson, Barbosa-Morais and colleagues compared binding patterns in the human chromosome and its mouse equivalent (equivalent means with a common ancestor and containing genes with similar functions) in Tc1 mouse liver cells, and again in both these chromosomes but in human and mouse normal liver cells respectively.
To their surprise, the behaviour of the transcription factors in the human chromosome 21– so their binding patterns to the different activator/suppressor zones in the DNA – was the same, whether this chromosome was in Tc1 or human hepatic cells, while very different from the patterns seen on its equivalent mouse chromosome. Furthermore, other markers of gene expression, as well as the RNA produced, were also very similar whether chromosome 21 was in human or Tc1 hepatic cells.
In conclusion, Wilson, Barbosa-Morais, Odom and colleagues’ results showed that the human chromosome, despite being in a full mouse environment, still behaved in “a human form”, showing that gene regulation is mostly the result of DNA regulatory sequences, at least in liver cells. Factors like cellular environment, DNA packing, outside cues or even the nature of transcription factors – as we see here, mouse transcription factors have no problems working in human DNA – all previously believed to affect regulation, are shown to have little effect on gene expression.
If this result is proved to be a generalised characteristic of cells, it is a finding that will question a series of widespread believes and strategies of biology. For example, one way scientists search for new active (or functional) genes is by looking for similar sequences in corresponding chromosomes of different species. What Wilson, Barbosa-Morais, Odom and colleagues’ results reveal that it is that those sequences that are not shared between species that ultimately determine if a gene is functional or not , implying that a much more detailed analysis of the DNA needs to be done to effectively understand our genetic blueprint.
Tissue and organ growing, and even cloning, are just some of the fields that can be potentially affected by these results. For example, it has been seen that if we collect all the transcription factors in a kidney cell and transfer them to a brain cell (where we inactivate all its brain-specific transcription factors) we could turn the brain cell into a kidney one. Or that if we put a “pro-cell” in a specific cellular environment it could develop into the cell and tissue corresponding to that environment. The new data by Wilson and colleagues - indicating that DNA regulatory sequences are the major force behind gene regulation - bring a new player into tissue and organ development, and although apparently making things more complicated, it will, no doubt, contribute to a better comprehension of the mechanisms behind cell specialisation.
Finally, these results can be important to understand better the mechanism behind disorders with a genetic origin whatever neurodegenerative and development diseases or even cancer. Like Barbosa-Morais says: “in diseases like cancer our work alerts for the crucial need to focus on risk factors in the DNA sequence and not just on examining developmental changes in the cell”.
When the genome started to be sequenced in the 1990s scientists knew that we were still very far from fully identifying our genes, and even further from understanding their function, but only in the last 10 years we have come to realise the real complexity behind gene expression. In fact, while less than 3% of the human DNA seems to be genes, more and more DNA (and RNA) that are not expressed into proteins - so not “real” genes –are discovered to affect gene expression. Transcription factors, on the hand, are now believed to be around 10% of all genes suggesting that the number of binding combinations switching genes on or off is also very large and will need a lot of work to be fully understood. Although we are still a long way to fully understand the intricacies of gene expression, Wilson, Barbosa-Morais, Odom and colleagues’ research is no doubt an important step in the right direction
Piece by Catarina Amorim (catarina.amorim at linacre.ox.ac.uk)Contacts for the authors of the original paper
Catarina Amorim | alfa
New catalyst controls activation of a carbon-hydrogen bond
21.11.2017 | Emory Health Sciences
The main switch
21.11.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
21.11.2017 | Physics and Astronomy
21.11.2017 | Physics and Astronomy
21.11.2017 | Life Sciences