Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species

Binding Site Turnover Produces Pervasive Quantitative Changes in Transcription Factor Binding between Closely Related Drosophila Species
Robert K. Bradley, Xiao-Yong Li, Cole Trapnell, Stuart Davidson, Lior Pachter, Hou Cheng Chu, Leath A. Tonkin, Mark D. Biggin, Michael B. Eisen
PLoS Biol 8(3): e1000343. doi:10.1371/journal.pbio.1000343

Changes in gene expression play an important role in evolution, yet the molecular mechanisms underlying regulatory evolution are poorly understood. Here we compare genome-wide binding of the six transcription factors that initiate segmentation along the anterior-posterior axis in embryos of two closely related species: Drosophila melanogaster and Drosophila yakuba. Where we observe binding by a factor in one species, we almost always observe binding by that factor to the orthologous sequence in the other species. Levels of binding, however, vary considerably. The magnitude and direction of the interspecies differences in binding levels of all six factors are strongly correlated, suggesting a role for chromatin or other factor-independent forces in mediating the divergence of transcription factor binding. Nonetheless, factor-specific quantitative variation in binding is common, and we show that it is driven to a large extent by the gain and loss of cognate recognition sequences for the given factor. We find only a weak correlation between binding variation and regulatory function. These data provide the first genome-wide picture of how modest levels of sequence divergence between highly morphologically similar species affect a system of coordinately acting transcription factors during animal development, and highlight the dominant role of quantitative variation in transcription factor binding over short evolutionary distances.

Author Summary
The differentiation of cells, tissues, and organs during animal development is established by a process in which genes that control cell identity and behavior are turned on and off at specific times and places. This process is choreographed, to a large extent, by a collection of proteins known as transcription factors that bind to specific sequences in DNA and thereby modulate the expression of neighboring genes. Because of the central role that transcription factors play in shaping organismal form and function, they have long been suggested to be major players in phenotypic evolution. However, we have a poor understanding of how changes to DNA affect transcription factor binding in living systems. Here, we use a combination of biochemical and genomic techniques to compare, between two closely related species of fruit flies in the genus Drosophila, the binding of six transcription factors that help establish the characteristic segments that form along the anterior-posterior (head to tail) axis in developing flies. We show that the patterns of transcription factor binding between these closely related species are broadly conserved, consistent with the nearly identical development and appearance of these species. However, we also show that, whereas the DNA changes that have accumulated between these species in the five million years since their divergence—roughly one difference per 10 basepairs—have not altered the locations where these factors bind, they have had a considerable effect on the amount of factor bound at each site across a population of embryos. We can trace these quantitative differences in binding to the gain and loss of the short sequences known to be preferentially recognized by these factors, giving us key insights into the effect that sequence changes have on the biochemical events that underlie animal development.

  1. #1 par dave tribbett le avril 9, 2010 - 10:10

    Great post, I just developed a post here that describes the results of a recent Stanford study describing transcription factors.

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