DNA repeats hold RNA starts

DNA sequences that don't code for proteins and are repeated thousands or millions of times in the genome are more than just genomic deadwood: These regions contain promoter sequences that can instigate not only their own transcription, but the transcription of protein-coding genes as well, a study published online in Nature on Sunday (April 19th) reports. The paper is likely to spur a slew of new research into repetitive elements in the genome, said Philip Kapranov, principal genomicist at linkurl:Helicos BioSciences;http://www.helicosbio.com/ in Cambridge, MA, who wrote a commentary to the study to be published today in Genome Biology. "As a class [repetitive elements] are not just a junk DNA. They're not just parasites, but they can shape the architecture of the genome," he said. Repetitive elements such as retrotransposons -- sequences of DNA that can pop out of the genome, multiply with an RNA intermediate and then pop back in a different location -- are sometimes called jumping genes. Some of these sequences are replicated about a million times throughout the genome, but they have generally been considered non-functional. Despite the fact that repeat sequences make up about 50% of the genome, "our technologies were unable to interrogate those sequences" until now, said linkurl:Thomas Gingeras;http://gradschool.cshl.edu/staff/gingeras_.html of Cold Spring Harbor Laboratory, who was not involved in the research. "We've had a convenient excuse to cut the genome in half," he said, and ignore these seemingly non-functional stretches of repeat sequences. linkurl:Piero Carninci;http://genome.gsc.riken.jp/osc/english/members/Piero_Carninci.html at the Omics Science Center of the RIKEN Institute in Japan and his colleagues used a novel technique called Cap Analysis Gene Expression (CAGE) to search for all of the transcriptional start sites in the genome. In CAGE tagging, the first 20 nucleotides or so of all of the RNA containing 5' caps (an important post-transcriptional modification that stabilizes the RNA molecule) are sequenced, and those sequences are mapped to the genome. Sequences marked by cap-associated RNA are considered the "hallmark of a true initiation site," said Kapranov. The method helped the investigators uncover unexpected start sites: They found over 200,000 transcription start sites within retrotransposons across the mouse and human genomes. Not only were these start sites initiating the transcription of the retrotransposons, but they were also affecting downstream protein-coding genes. "These RNAs provide alternative promoters," Carninci told The Scientist in an email. What's more, there was a pattern to the protein-coding gene regulation. The researchers found that certain families of repetitive elements were present in specific tissue type. For example, one family of repetitive elements in the mouse was found in many tissues, but absent from the brain, hypothalamus, neuroblastoma and embryonic tissues. "Although the general idea is that retrotransposons are passive elements of the genome, or even harmful, cells have learned how to use them in a symbiotic" fashion by making use of the sequences' start-sites, Carninci explained The data was collected as part of a larger effort called the Functional Annotation of Mouse (FANTOM) project, a consortium organized by researchers at the RIKEN Institute and initiated in 2000 to look at the full length cDNA library. The study was published alongside two other papers from the FANTOM project. One paper, authored by linkurl:John Mattick;http://www.imb.uq.edu.au/?page=12238 from the University of Queensland, Australia, and colleagues, compared sequences from the FANTOM data set to similar data in chicken and flies, and found small RNAs associated with initiation start sites in these other species. The study added to the body of evidence for the existence of a new group of RNA, which the researchers called transcription initiation RNA (tiRNA), and suggested an evolutionarily conserved role for these tiny, 18-nucleotide-long elements. The third paper from the FANTOM consortium, led by the Riken Institute's Yoshihide Hayashizaki, lent support to the concept that there are redundant transcription factors for genes regulating development. While researchers have often focused on finding the master regulator -- the highest level controller of a gene program - new evidence is pointing to the existence of cassettes redundant transcription factors that promote transcriptional initiation, said Gingeras. While the transcription of more than 200,000 repetitive RNAs and their association with protein coding genes is compelling, the real test, said Kapranov, will be to study "how many of the transcripts are functional," and whether and to what degree these sequences affect phenotype. **__Related stories:__***linkurl:Mining mammalian genes;http://www.the-scientist.com/article/display/53761/ [November 2007]*linkurl:The human genome: RNA machine;http://www.the-scientist.com/2007/10/1/61/1/ [October 2007]*linkurl:The Human Genome Project, +5;http://www.the-scientist.com/article/display/23065/ [February 2006]

DNA repeats hold RNA starts

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