Assumptions and premises are of fundamental importance when making inferences. We often discuss them -if at all- just the once, and afterwards take them for granted in our reasoning. It may be the case, though, that they are not correct, which can potentially invalidate the inferences we make on the basis of those premises.

For instance, when walking in Karls Jonas Gate, the main street of the shopping downtown in Oslo, I happened to notice many unusually dressed young people. The inference I made from that observation was that citizens of Oslo were, to say the least, very original. I then kept reasoning for the four days of EACR with that assumption in mind, to then find out at the end of my stay that Oslo was at the center of the Norwegian 'Skeive Dager' (the Gay Pride Festival) for that weekend, and prove my assumption wrong. To say the truth, I could have reasoned it out by noticing the rainbow flags that were hanging everywhere in town, but I had not paid enough attention, and did not take that piece of evidence into account when extrapolating from my observations.

In a different context but in the same city, Duncan Odom also discussed the importance of premises in our reasoning. His talk at EACR focused on the assumption underlying a good deal of cancer research performed in mice, namely that murine and human transcription factors bind to the same regions of the genome. As put by Odom, it is almost impossible to stress enough the importance of transcription in cancer, as most if not all tumors are characterized by deregulation in transcription. But what if this premise were not correct? This would have important consequences on all the inferences we make on experiements done in mice, and the extrapolations we make on our species would need to be revised.

Odom, who was awarded the EMBO young researcher investigator in 2008, leads the Regulatory Systems Biology Laboratory at the Cancer Research UK Cambridge Research Institute, devoted to understanding the systems-level transcriptional mechanisms underlying mammalian cell specification, which are often perturbed in different diseases, such as cancer and diabetes.

The application of new genome-wide methodologies has only started redefining our understanding of when and where mammalian transcription factors interact with DNA, thereby providing new insight into the mechanisms of transcriptional evolution.[1] But the evolution of mammalian transcriptional regulation remains largely unexplored beyond limited mouse-human comparisons, and understanding the evolutionary dynamics of transcription factor (TF) binding is essential to assess the evolution of gene regulation. Therefore, Odom's lab set out to test whether transcription factor binding sites actually diverge more rapidly than what we think -or would like to think- between mice and humans.

His group chose the liver as a model organ and combined chromatin immunoprecipitation with high-throughput sequencing to determine the genome-wide occupancy of two TFs, i.e. the CCAAT/enhancer-binding protein alpha (CEBPA) and the hepatocyte nuclear factor 4 alpha (HNF4A). Five vertebrates were used as model organisms: human, mouse, dog, short-tailed opossum, and chicken. CEBPA and HNF4A were selected as representative Tfs, as both are conserved and constitutively expressed with well-characterized target genes. Experiments performed by Odom's group showed that, although each TF displays highly conserved DNA binding preferences, most binding is species-specific, and aligned binding events present in all five species are rare.[2]

In general, the results obtained by Odom's group reveal large interspecies differences in transcriptional regulation. By doing so, they provide insights into regulatory evolution. Not only that, but they are also particularly relevant as changes in gene expression directed by transcriptional regulators can give rise to new physiological or pathological phenotypes.

Take home message: never take your assumptions for granted, and take some time to revise them every now and then. You may come up with unexpected findings, which may lead you to revise your beliefs.

References

[1] Wilson MD, Odom DT. Evolution of transcriptional control in mammals. Curr Opin Genet Dev 2009;19(6):579-85.

[2] Schmidt S, Wilson MD, Ballester B, et al. Five-Vertebrate ChIP-seq Reveals the Evolutionary Dynamics of Transcription Factor Binding. Science 2010; 328(5981):1036-1040.