Transcription Initiation Sites: Do You Think This Is Reasonable?

I'm interested in how scientists read the scientific literature and in how they distinguish good science from bad science. I know that when I read a paper I usually make a pretty quick judgement based on my knowledge of the field and my model of how things work. In other words, I look at the conclusions first to see whether they conflict with or agree with my model.

Many of my colleagues do it differently. They focus on the actual experiments and reach a conclusion based on how the perceive the data. If the experiments look good and the data seems reliable then they tentatively accept the conclusions even if they conflict with the model they have in their mind. They are much more likely to revamp their model than I am.

I'm about to give you the conclusions from a recently published paper in Nature. I'd like to hear from all graduate students, postdocs, and scientists on how you react to those conclusions. Do you think the conclusions are reasonable (as long as the experiments are valid) or do you think that the conclusions are unreasonable, indicating that there has to be something wrong somewhere?

The paper is Venters and Pugh (2013). It's title is Genomic organization of human transcription complexes. You don't need to read the paper unless you want to get into a more detailed debate. All I want to hear about is your initial reaction to their final two paragraphs.

Consolidated genomic view of initiation

...The discovery that transcription of the human genome is vastly more pervasive than what produces coding mRNA raises the question as to whether Pol II initiates transcription promiscuously through random collisions with chromatin as biological noise or whether it arises specifically from canonical Pol II initiation complexes in a regulated manner. Our discovery of ~150,000 non-coding promoter initiation complexes in human K562 cells and more in other cell lines suggests that pervasive non-coding transcription is promoter-specific, regulated, and not much different from coding transcription, except that it remains nuclear and non-polyadenylated. An important next question is the extent to which transcription factors regulate production of ncRNA.

We detected promoter transcription initiation complexes at 25% of all ~24,000 human coding genes, and found that there were 18-fold more non-coding complexes than coding. We therefore estimate that the human genome potentially contains as many as 500,000 promoter initiation complexes, corresponding to an average of about one every 3 kilobases (kb) in the non-repetitive portion of the human genome. This number may vary more or less depending on what constitutes a meaningful transcription initiation event. The finding that these initiation complexes are largely limited to locations having well-defined core promoters and measured TSSs indicates that they are functional and specific, but it remains to be determined to what end. Their massive numbers would seem to provide an origin for the so-called dark matter RNA of the genome, and could house a substantial portion of the missing heritability.

Looking forward to hearing from you.

Keep in mind that this is a Nature paper that has been rigorously reviewed by leading experts in the field. Does that influence your opinion?

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Venters, B.J. and Pugh, B.F. (2013) Genomic organization of human transcription initiation complexes. Nature Published online 18 September 2013 [doi: 10.1038/nature12535] [PubMed] [Nature]