Researchers create atlas over gene usage in all human cell types
In the large-scale international FANTOM5 project, researchers from around the world have created an atlas that shows which different genes that are used in virtually all cell types that humans are composed of. Five research groups from three different departments at Karolinska Institutet have participated in the work, which was presented today with coordinated publications in several scientific journals, including Nature and Blood.
After several years of work by more than 250 researchers in 114 laboratories in more than 20 countries, the FANTOM5 Consortium is today publishing a series of related articles in ten journals, including two core papers in Nature. The FANTOM (functional annotation of the mammalian genome) project was initiated at RIKEN in Japan in 2000 with the aim of building a comprehensive gene catalogue using cDNA technology. The project has since evolved and reached a fifth stage and is closing in on the answer to the question of what is written in our genetic material.
Humans are complex beings that are composed of at least 400 different kinds of cells. Although they all have an identical genome, and therefore the same genes, cell types look different and have different functions. What distinguishes all of these cell types is which parts of the genome they use. For example, a brain cell uses different genes than liver cells and therefore acts very differently.
“In FANTOM5 we have for the first time in a systematic way investigated exactly which genes are used in virtually all cell types in the human body, and the regions that determine which genes are used,” says Alistair Forrest, who has led the consortium from RIKEN in Yokohama, Japan.
Possible to identify enhancers
The sequencing technique used in the project has made it possible to identify the regions of DNA, known as “enhancers” that govern the use of the genes. Their function is to regulate a gene, ensuring that it is only active in specific cell types. Until now it has only been possible to map the enhancers in a handful of cell types. Thanks to new technology, researchers in FANTOM5 have been able to identify the activity of the enhancer regions in all cells and tissues, and then link them to gene activity in the same cells. The research groups discovered that many mutations that are linked to diseases are situated in enhancer regions. This means you can link mutations to changes in gene regulation.
“As the method can be used on samples from patients, this opens up great opportunities to understand what is going wrong at a molecular level in tissue from sick people,” says Albin Sandelin, who has a PhD from Karolinska Institutet and is now a professor at the University of Copenhagen and head of the enhancer study.
One example of such an analysis has been led by Andreas Lennartsson and Karl Ekwall at the Department of Biosciences and Nutrition at Karolinska Institutet. In the study, the results of which are published in Blood, the researchers have investigated how our most common immune cell, the neutrophil, is formed. It was shown that epigenetic changes – i.e. chemical changes in DNA that do not affect the actual DNA sequence – often occur in enhancer regions in neutrophils, compared to other regions.
“With this method of identifying enhancer regions, we have discovered that there is a link between epigenetic regulation and enhancers that are activated during neutrophil maturation,” says Michelle Rönnerblad at the Department of Biosciences and Nutrition at Karolinska Institutet, who conducted the studies in the blood of humans.
The researchers believe that their findings may increase our knowledge of, for example, acute leukaemia, a form of cancer of the blood.
“Acute leukaemia occurs when blood cell development is blocked somewhere along the way, which leads to many immature, non-functional cells forming in the blood. It is therefore important to understand what regulates haematopoiesis in order to identify new ways of treating leukaemia,” says Andreas Lennartsson.
The researchers from Karolinska Institutet who are members of the FANTOM5 Consortium are Karl Ekwall, Andreas Lennartsson, Juha Kere, Helena Persson and Carsten Daub (also affiliated to RIKEN) at the Department of Biosciences and Nutrition, Morana Vitezic and Lukasz Huminiecki at the Department of Cell and Molecular biology and Peter Arner and Niklas Mejhert at the Department of Medicine, Huddinge. FANTOM5 was made possible through a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology, while the EU and a number of other research funders have also contributed.
- “A promoter level mammalian expression atlas”, Alistar Forrest et al., Nature 27 March 2014, doi:10.1038/nature13182.
- “An atlas of active enhancers across human cell types and tissues”, Robin Andersson et al., Nature 27 March 2014, doi:10.1038/nature12787.
- “High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis”, Punit Prasad et al., Blood 27 March 2014, doi:10.1182/blood-2013-02-483537.
- “Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation”, Michelle Rönnerblad et al., Blood 27 March 2014, doi:10.1182/blood-2013-02-482893.
- “Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells”, Erik Arner et al., PLOS ONE 27 March 2014, doi:10.1371/journal.pone.0080274
- A list of all 18 publications can be found on the FANTOM website.