An extended atlas of transcription initiation sites (TSSs) has been described by the functional annotation of the mammalian genome 5 (FANTOM5) consortium in a recent article on Nature1. It is a comprehensive overview of expression profiles in mice and humans complementing and extending the information already present in other datasets, such as ENCODE2.
The large international FANTOM consortium led by RIKEN PMI has performed cap analysis of gene expression (CAGE)3 —a technique that sequences the 5’ of the RNA messenger —on a large cohort of mouse and human samples: 573 human primary cells, 128 mouse primary cells, 250 cancer cells lines, 152 human post-mortem tissues, and 271 mouse tissue samples. They found more than three million peaks in humans and more than two million in mice, including sequences in internal exons. To reduce the background, they applied tag evidence threshold. The TSSs found were confirmed to belong to known promoters, based on known sequence analyses— expressed sequence tags, histone H3 lysine 4 trimethylation marks and DNase hypersensitive sites. The peaks were classified as non-ubiquitous/cell-type specific (cell-adhesion and signal transduction), ubiquitous-uniform/housekeeping (ribonucleoprotein complex and RNA processing), and ubiquitous non-uniform (cell cycle genes). Most of the peaks belong to cell-type specific genes, highlighting the abundance of tissue specific gene regulation; also, the housekeeping genes are the most conserved between human and mouse, confirming the importance of their function. Although some level of conservation, only 43% of human TSSs could be aligned to the mouse genome and only 39% of mouse TSSs could be aligned to the human genome, thus indicating a remodeling of transcription initiation during evolution.
This is research offers more than a collection of information. For instance, it also analyzed TSSs in cancer cells opposed to primary cells, finding that transcription factors are more expressed in the transformed than in the primary cells, because of chromosomal rearrangements and mutations; this highlights an underestimated problem of using cancer cells for transcription studies.
The FANTOM5 atlas provides an extensive collection and material on TSSs, which is available online (http://fantom.gsc.riken.jp/5) together with specialized tools (ZENBU3 or SSTAR)3 to analyze the data and integrate the information from the ENCODE and the FANTOM consortium datasets, thus allowing scientists to have the access to a huge amount of information on mammalian gene regulation.
1FANTOM Consortium and the RIKEN PMI and CLST (DGT). (2014) A promoter-level mammalian expression atlas.Nature 507(7493):462-70. doi: 10.1038/nature13182.
2ENCODE Project Consortium, Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, et al. (2007).“Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project”. Nature 447 (7146): 799–816. .doi:10.1038/nature05874
3 Shiraki T, Kondo S, Katayama S, Waki K, Kasukawa T, Kawaji H, Kodzius R, Watahiki A, Nakamura M, Arakawa T, Fukuda S, Sasaki D, Podhajska A, Harbers M, Kawai J, Carninci P, Hayashizaki Y. (2003) Cap analysis gene expression for high-throughput analysis of transcriptional starting point and identification of promoter usage”. Proc Natl Acad Sci U S A. 100 (26): 15776–81.. doi:10.1073/pnas.2136655100.
4Jessica Severin, Marina Lizio, Jayson Harshbarger, Hideya Kawaji, Carsten O Daub, Yoshihide Hayashizaki, the FANTOM consortium, Nicolas Bertin, and Alistair RR Forrest. (2014) “Interactive visualization and analysis of large-scale NGS data-sets using ZENBU”. Nature Biotechnology,