Analysis: Evolution of transcription-factor binding and cell-cycle-regulated transcription

Together with collaborators in Søren Brunak’s group, I have earlier published a comparative study on eukaryotic cell-cycle regulation. In the supplement and earlier papers, we presented benchmarks that documented the sensitivity with which periodically expressed genes can be identified based on microarray expression data. We thereby showed that the poor evolutionary conservation of transcriptional cell-cycle regulation is not an artifact of individual gene lists being unreliable.

However, there is a more direct test that we did not think of at the time, namely to check if the changes in periodic transcription agree with the binding of cell-cycle transcription factors in each organism. The first step is to select two organisms (organism 1 and organism 2) and extract two sets of genes: 1) cycling genes from organism 1 with non-cycling orthologs in organism 2 and 2) non-cycling genes from organism 1 with cycling orthologs in organism 2. Next, Fisher’s exact test is used to determine if targets of cell-cycle transcription factors are overrepresented in the first set relative to the second. This procedure is equivalent to the test for coevolution between transcriptional and postranslational regulation (see Jensen et al. (2006) for details).

I used the procedure to perform all pairwise tests for Homo sapiens, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Arabidopsis thaliana. For each choice of organism 1, I used the same set of cell-cycle transcription-factor targets also used for the original benchmarks. The table below sumarizes the results of the statistical tests; the rows specify organism 1 and columns specify organism 2:

  H. sapiens S. cerevisiae S. pombe A. thaliana
H. sapiens   P < 10-5 P < 10-9 P < 10-6
S. cerevisiae P < 10-8   P < 10-7 P < 0.01
S. pombe P < 10-4 n.s.   P < 0.01
A. thaliana P < 0.09 n.s. P < 10-4  

For most of the pairwise organism comparisons, the expected coevolution of transcription factor binding and cell-cycle-regulated transcription is supported by the statistical test. Benjamini-Hochberg correction for multiple testing was thus not performed as it would change the p-values only marginally (by a factor of 4/3 to be exact). Apart from the S. pombe vs. S. cerevisiae comparison, the weak correlations all involve A. thaliana for which only very limited microarray expression data is available.

This analysis shows that the differences in cell-cycle-regulated transcription (as measured by microarrays) are consistent with the available data on transcription-factor binding. This provides direct evidence that the poor conservation of cell-cycle regulation observed between eukaryotes is due to genuine, biological differences.

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