Map of how DNA controls cells may boost gene therapies

 作者:鄂瑜     |      日期:2019-02-26 08:09:02
By Michael Slezak The clearest map yet of how genes control cells to make our bodies work has been drawn up. The map is challenging ideas about what our genes do and may accelerate the development of gene-based therapies. Every cell in your body contains the same genetic code. But which genes are active, or “expressed”, in the cell depends on its function – whether it’s a neuron or a red blood cell, for example. Which genes are expressed is controlled by tiny bits of the genome called promoters and enhancers. An international consortium of researchers known as FANTOM, led by the RIKEN institute in Japan, has uncovered which promoters and enhancers are used by which cells. By looking at more than 800 human tissue samples, covering nearly all cell types, they found 44,000 enhancers and 180,000 promoters that control gene expression. The pattern of enhancers and promoters active in each cell defines which parts of the genome it uses, effectively defining the nature of the cell itself. “This pattern is the most objective definition of the cell,” says Yoshihide Hayashizaki, who leads the consortium. The latest work has been published across 18 papers in journals including Nature, Blood and BMC Genomics. The team combined the map with data from studies comparing the genomes of sick and healthy people, known as genome-wide association studies (GWAS). Surprisingly, this showed that mutations linked to disease occur more often in the DNA responsible for the enhancers and promoters than in the gene variants themselves. Geneticist Thomas Preiss of the Australian National University in Canberra, who is not involved in the FANTOM collaboration, says this knowledge “breathes new life” into GWAS because until now researchers only knew how to interpret the results if the identified mutation was in the gene variant. He describes the map as a profound new understanding of enhancer and promoter function. The hope is that researchers around the world can now try to pin down which genetic mutations in the promoters and enhancers are actually linked to disease and design therapies to target them. Hayashizaki says the FANTOM group has already used the data to find gene-expression patterns that predict the spread of colon cancer, and will submit these results to a journal soon. He thinks the finding could help treat people within three years. Other insights gleaned from the FANTOM collaboration include the confirmation that most of our genome is there to govern specific cell behaviour, rather than behaviours common to all cells. “We’re large, complex organisms,” says Alistair Forrest of the RIKEN Omics Science Center in Yokohama City. The vast majority of the genome helps cells do their own tissue-specific functions, he says. Only 20 per cent of our genes appear to be responsible for making things like cell scaffolds and other functions common to all cells. “This work further shows how complex gene regulation is,” says Guy Barry from the Garvan Institute of Medical Research in Sydney, Australia. “There will be much more uncovered in the future as this is likely the tip of the iceberg.” Journal references: Nature, DOIs: 10.1038/nature13182 and 10.1038/nature12787 More on these topics: