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 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 in 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 combination 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



Article: Michael D. Wilson, Nuno L. Barbosa-Morais, Dominic Schmidt, Caitlin M. Conboy, Lesley Vanes, Victor L. J. Tybulewicz, Elizabeth M. C. Fisher, Simon Tavaré, Duncan T. Odom, 'Species-Specific Transcription in Mice Carrying Human Chromosome 21', Originally published in Science Express on 11 September 2008, Science 17 October 2008: Vol. 322. no. 5900, pp. 434 - 438 DOI: 10.1126/science.1160930