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Generation of complex gene architectures in the human genome

Intense investigations during the past 10-15 years have revealed that the human genome is transcribed in a manner that is much more complicated than previously appreciated. A collaboration between researchers from Aarhus and Copenhagen now reveals some underlying principles leading to such promiscuous genome activity.

1) Gene promoters that are far away from other genes typically produce transcripts on both strands. The PROMoter uPstream Transcript (PROMPT) is short and rapidly degraded due to special DNA sequence patterns around the PROMPT and which are not present at the gene start site. Thus, the gene product is typically a stable mRNA. 2) If two gene start sites share a common promoter, no PROMPTs are produced. Both genes start sites produce stable RNAs. 3) If two gene promoters are closely positioned, PROMPTs are produced, but are stabilized because the DNA signals necessary for their degradation cannot form because the gene promoters are too close. Instead, the PROMPTs grow longer and are stable, which in effect creates longer mRNA variants from the two gene start sites. 4) If gene promoters are sufficiently separated, their DNA patterns do not influence their neighboring PROMPTs, which remain short and unstable, much like in the first case above.

The laboratories of Torben Heick Jensen at Aarhus University and Albin Sandelin at the University of Copenhagen previously established that the large majority of human genes give rise to transcription on both strands from their transcription start sites, typically producing an mRNA on the forward strand and a rapidly degraded transcript, called a promoter upstream transcript (PROMPT), on the reverse strand (see Figure). The degradation of PROMPTs is linked to DNA sequence patterns not found in the mRNA gene region and ensures that the overall output from promoters is primarily that of mRNA.

However, the human genome is complex: genes are often co-localized with their promoters very close to each other. In the present study, published in Nature Genetics, the research groups of Heick Jensen and Sandelin collaborated with scientists at the MIT, Stanford University and the EMBL to delineate the biogenesis of PROMPTs in such complex regions and found that if gene start sites are close, PROMPTs are generated, but will not be degraded because the limited space between gene promoters does not allow for the presence of DNA sequence patterns necessary for PROMPT decay. Instead, PROMPTs grow longer and in effect establish longer products from the two neighboring gene promoters.

More generally, in investigating this process, the teams could define general rules for gene transcription, PROMPT generation and the creation of new gene start sites, from which evolution can shape the transcriptional activity of genomes. These general principles may help explain the vast complexity of the human genome and provide models for how genes and entire genomes evolve over time - models which can now be tested.

Link to the scientific article in Nature Genetics.

For further information, please contact

Professor Torben Heick Jensen 
Department of Molecular Biology and Genetics
Centre for mRNP Biogenesis and Metabolism
Aarhus University, Denmark
thj@mb.au.dk - mobile: +45 60202705