Researchers at the Wayne State University School of Medicine are among more than 250 scientists in 114 labs in more than 20 countries and regions to publish a series of coordinated papers, including landmark papers in Nature and ten other journals, revealing a definitive list of human cell states that has the potential to serve as an essential resource for regenerative medicine.
Detroit resident Leonard Lipovich, Ph.D., an associate professor in both the Center for Molecular Medicine and Genetics and the Department of Neurology, is among the authors. His lab is the only contributing lab from Michigan.
Dr. Lipovich is a co-author of the paper "A Promoter Level Mammalian Expression Atlas," which will appear in the March 27 issue of Nature. The work provides the first ever quantitative definition of the complete set of human and mouse gene promoters at single-base resolution.
The Functional Annotation of the Mammalian Genome (FANTOM) project is an initiative by RIKEN, Japan’s largest research institute for basic and applied research, and was launched in 2000, originally to build a complete gene catalogue with cDNA technologies (http://fantom.gsc.riken.jp/). The project now analyzes the mammalian transcriptome – the complete set of all RNA molecules produced in one or a population of cells – using next-generation sequencing.
Dr. Lipovich has been a contributing member of the FANTOM project since 2004 and previously co-authored four papers with the consortium: two in Science in 2005 and two in PLoS Genetics in 2006.
“What is written in the genome? That was our ultimate goal since we have launched the consortium. The basic library of cell definition that was produced during FANTOM5 is a remarkable step to understanding life. The library will be an essential resource for developing regenerative medical techniques in the near future,” said Dr. Yoshihide Hayashizaki, FANTOM’s general director.
This is stage five of the effort, and provides the first holistic view of transcriptional regulatory network models for the majority of the cell types that make up a human. RIKEN organizers recruited a multidisciplinary network of experts in primary cell biology and bioinformatics to do this, including Dr. Lipovich and two of his lab members: former WSU postdoctoral researcher Hui Jia, Ph.D., and WSU doctoral candidate Emily Wood.
The Nature papers describe maps of promoters and enhancers encoded in the human genome, and their activity across the vast wealth of human cell types and tissues of the human body. The entire list of the articles will be available at http://fantom.gsc.riken.jp/papers/
The experiments relied on the evolution of Cap Analysis of Gene Expression, a key method developed by RIKEN. Researchers including Dr. Lipovich and his WSU team identified more than 180,000 promoters and 44,000 enhancers on the genome across more than 180 human primary cells. The majority of these transcriptional regulation regions is highly specific to a cell type.
“We are complex multicellular organisms composed of at least 400 distinct cell types. This beautiful diversity of cell types allow us to see, think, hear, move and fight infection, yet all of this is encoded in the same genome,” said Alistair Forrest, Ph.D., scientific coordinator of FANTOM5. “The difference between all these cells is what parts of the genome they use – for instance, brain cells use different genes than liver cells, and therefore they work very differently. In FANTOM5, we have for the first time systematically investigated exactly what genes are used in virtually all cell types across the human body, and the regions which determine where the genes are read from the genome.”
Unlike other large-scale genomics projects, the team focused on normal primary cells rather than cell lines derived from cancers. “In FANTOM5 we made the decision early on that we should include a large focus on normal primary cells and tissues. Although cell lines are easy to use, they are seldom good models of normal cells,” Dr. Forrest said.