Whereas the human genome project mapped every gene in the human genome, the FANTOM project has been mapping which genes are active. And now, with the culmination of the project’s fifth stage, FANTOM has released the most detailed picture yet of how human genetic material is regulated. The work amounts to a grand circuit diagram of the network of switches, built into human DNA, that controls when and where genes are turned on and off.

Two landmark papers appeared March 26 in Nature, accompanied by 16 studies published in Nature Biotechnology, Genome Research, Blood, Molecular Biology and Evolution, Proceedings of the National Academy of Sciences, Nucleic Acids Research, Molecular Genetics and Metabolism, BMC Genomics, and PLoS ONE.

The papers published in Nature describe maps of promoters and enhancers—short regions of DNA that influence the activity of genes—encoded in the human genome, and their activity across the vast wealth of human cell types and tissues of the human body. Together with the other studies published by FANTOM5, this data provides the first complete view of the networks regulating transcription across all cell types.

The FANTOM project (for functional annotation of the mammalian genome) is a RIKEN initiative launched in 2000 to build a complete library of human genes using the capabilities offered by new, state-of-the-art cDNA technologies. Over 250 experts in primary cell biology and bioinformatics from 114 institutions based in more than 20 countries and regions worked as part of FANTOM5. The researchers involved in the two Nature papers used a highly sensitive technique called cap analysis of gene expression (CAGE), developed at RIKEN, to monitor the activity of promoters and enhancers.

The first Nature paper (“An atlas of active enhancers across human cell types and tissues”) presents an atlas of active, in vivo bidirectionally transcribed enhancers across the human body: “Based upon the FANTOM5 CAGE expression atlas encompassing 432 primary cell, 135 tissue, and 241 cell line samples from human, we identify 43,011 enhancer candidates and characterize their activity across the majority of human cell types and tissues.” The researchers indicated that the activity of the large majority of these transcriptional regulation regions is highly specific to cell type.

The authors report using the atlas to “compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers.” In addition, the authors explored the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The authors concluded that the FANTOM5 enhancer atlas, which is available online, represents a unique resource for studies on cell-type-specific enhancers and gene regulation.

The second Nature paper (“A promoter level mammalian expression atlas”) used single-molecule sequencing to map human and mouse transcription start sites and their usage in a panel of distinct human and mouse primary cells, cell lines, and tissues to produce the most comprehensive mammalian gene expression atlas to date. According to a Nature editor’s summary, the data provide “a plethora of insights into open reading frames and promotes across different cell types in addition to valuable annotation of mammalian cell-type-specific transcriptomes.”

The significance of having compiled an atlas of human gene expression was explained by Dr. Alistair Forrest, scientific coordinator of FANTOM5: “Humans 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. 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.”
Looking forward to applications inspired by FANTOM5's work, Dr. Yoshihide Hayashizaki, the general director of FANTOM, offerered these remarks: “The basic library of cell definition that was produced during FANTOM5 is a remarkable step to manipulating cells. The library will be an essential resource for developing a wide range of technologies for the life sciences, that will lead to the development of regenerative and personalized medicine in the near future.”
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