FANTOM stands for the Functional Annotation Of Mammalian genome and is an international research consortium founded in the year 2000 to assign functional annotations to the full-length complementary DNAs (cDNAs) that were collected during the Mouse Encyclopaedia Project at RIKEN. As of April 2009, 15 countries, and 51 institutions from Japan and other countries, participate in the FANTOM project.
Research at FANTOM has proceeded in three phases. FANTOM began with the establishment of the annotation pipeline that developed and expanded quickly into more functional analysis. We now range from transcriptome analysis to transcriptional factor network research, which is currently being carried out as part of FANTOM4.
- The consortium developed an effective system for functional gene annotation by designing appropriate rules and methods. The result was mainly published in Nature in 2001(Kawai et al. 2001). The paper was followed by the draft sequence of human genome (Lander et al. 2001) week later because they used our cDNA for gene number prediction.
During the second phase of the FANTOM activities, we determined the base sequences and assigned functional annotations to a set of 60,770 full-length mouse cDNAs. This was the first project worldwide to standardize full-length mammalian cDNAs. The research was published in a special issue of Nature on the decoding of the mouse genome in 2002 (Okazaki et al. 2002) We reported about 15,000 non-coding RNAs (of which only about 100 had been previously identified). The research was published in a special issue of Nature on the decoding of the mouse genome which was operated by Dr. Waterstone and co-workers (Waterston et al. 2002) They also used our cDNA for gene identification. In addition, 35 papers on detailed analysis using the obtained FANTOM2 dataset were published in the “FANTOM2 suite” in Genome Research in 2003.
- Besides working with full-length cDNAs, the FANTOM consortium utilized a new technology, CAGE, to reveal that more than 63% of the genome - instead of the known ~1.5% fraction of protein coding exons - is transcribed as RNA. We also confirmed the existence of over 23,000 non-coding RNAs (ncRNAs) and that >73% of the transcriptional units show sense-antisense transcription. This work, which was described as the discovery of “a new continent in the RNA world”, has resulted in the rewriting of textbooks in the field. This work was published in a couple of papers in the “RNA special issue” of Science in 2005 (Carninci et al. 2005; Katayama et al. 2005) Notably, of the eight papers in the issue, two others also referred to the FANTOM database (Jopling et al. 2005; Willingham et al. 2005)
- In FANTOM4 the focus has changed to understanding how these components work together in the context of a biological network. Using deepCAGE (deep sequencing with CAGE) we monitored the dynamics of transcription start site (TSS) usage during a time course of monocytic differentiation in the acute myeloid leukemia cell line THP-1. This allowed us to identify active promoters, monitor their relative expression and define relevant regions for carrying out transcription factor binding site predictions. Computational methods were then used to build a network model of gene expression in this leukemia and the transcription factors key to its regulation. This work gives the first picture of the wiring between genes involved in acute myeloid leukemia and provides a strategy for identifying key factors that determine cell fates.
In addition to the network, FANTOM4 data was used in two additional analyses. The first identified a novel class of short RNAs associated with transcription start sites and the second focused on the role of repetitive element expression in the transcriptome.
Global standard set up by FANTOM
The FANTOM database and full-length cDNA clone bank are regarded as new global standards in the life sciences. These FANTOM resources will continue to improve over time and should be of ongoing use to researchers worldwide. They serve as a platform for basic research on various organisms, including humans and mice, as well as for applied research in the fields of medicine and drug discovery.
- The FANTOM Database
- FANTOM full-length cDNAs have been derived from various mouse tissues at different developmental stages. The FANTOM3 database (http://fantom.gsc.riken.go.jp/) was accessed 2,600,674 times in the 6 months following its release, which means that it is being consulted approximately once every 5 seconds.
- Full-length cDNA clone bank
- The full-length cDNA clones are commercially available via Dnaform, Invitrogen, RZPD, and Gene Service. We distribute these cDNA clones without charge for collaborators. By 2005, RIKEN had distributed full-length cDNA clones to over 960 research groups.
- FANTOM technology applications
- The set of full-length cDNA technologies developed at the RIKEN and the cDNA annotation system established at FANTOM have also been used to analyze full-length cDNAs of rice (the staple food of Japan and many nations) (Kikuchi et al. 2003), Arabidopsis thaliana (a plant commonly used in laboratory research) (Seki et al. 2002b; Yamada et al. 2003), drosophila (Stapleton et al. 2002), xenopus, song bird (Wada et al. 2006), honeybee (InternationalHoneybeeConsortium 2006), and the human (Imanishi et al. 2004), as well as in many other organisms.
New science from FANTOM
- Induced pluripotent stem (iPS) cells
- A research group led by Professor Shinya Yamanaka at the Kyoto University, Japan, selected 24 factors from the FANTOM clone database for use as candidate initiation factors, based on the hypothesis that the initiation factors contained in embryonic stem (ES) cells are identical to those required to maintain their pluripotency and for multiplication (Takahashi et al. 2007). The group has subsequently shown that fibroblastic cells originating from adult mouse skin and fetal mice, as well as versatile stem cells from human skin, can be converted into iPS cells by combining four of these 24 factors.
- Allen Brain Atlas
- The Allen Institute for Brain Science in the United States has created a digital atlas that encompasses the whole brain, and has made it publicly available (http://brain-map.org/welcome.do). The atlas graphically illustrates the expression of genes within the mouse brain using Informatix software. This project has also made use of the FANTOM database. From among its full-length mouse cDNA clone set, researchers at the Allen Institute selected those derived from the brain, and analyzed their genome-wide expression through high-speed in situ hybridization. This approach has made it possible to survey the entire genome and to identify the genes that are expressed in specific areas within the brain. This brain atlas created using the FANTOM database will be a valuable source of information for various future research projects on brain function and organization.
- Application to plant science
- RIKEN Plant Science Center has performed cDNA microarray analysis, which was developed in collaboration with us, to obtain the gene expression pattern of Arabidopsis genes under drought, cold, or high-salinity conditions in order to identify the target genes of stress-related transcription factors. The information generated in this work has led to springboard for a new wave of strategies to improve plant tolerance of agriculturally important crops to dehydration, high salinity, and cold (Maruyama et al. 2004; Seki et al. 2002a).
Social aspects of FANTOM
One of the significant characters of the FANTOM consortium is its interdisciplinary focus. Expertise of molecular biology, medical science, pharmaceutical science, bioinformatics, mathematics, engineering, and even high-energy physics has been actively utilized. These interdisciplinary efforts gave rise to several other independent, collaborative projects among members of the consortium, targeting, for example, further validation experiments that went well beyond the data analysis for the main papers. FANTOM has also provided an opportunity for young researchers to work closely with a lot of leading scientists in various research areas. The FANTOM collaboration has been a kick-start to the careers of many researchers.