Nucleic Acids Research, 2002, Vol. 30, No. 5 1255-1261
© 2002 Oxford University Press
Nucleotides of transcription factor binding sites exert interdependent effects on the binding affinities of transcription factors
1Harvard University Graduate Biophysics Program, Harvard Medical School, Boston, MA 02115, USA, 2Harvard Medical School Department of Genetics, Alpert Building 514, 200 Longwood Avenue, Boston, MA 02115, USA and 3Harvard College, Cambridge, MA 02138, USA
We can determine the effects of many possible sequence variations in transcription factor binding sites using microarray binding experiments. Analysis of wild-type and mutant Zif268 (Egr1) zinc fingers bound to microarrays containing all possible central 3 bp triplet binding sites indicates that the nucleotides of transcription factor binding sites cannot be treated independently. This indicates that the current practice of characterizing transcription factor binding sites by mutating individual positions of binding sites one base pair at a time does not provide a true picture of the sequence specificity. Similarly, current bioinformatic practices using either just a consensus sequence, or even mononucleotide frequency weight matrices to provide more complete descriptions of transcription factor binding sites, are not accurate in depicting the true binding site specificities, since these methods rely upon the assumption that the nucleotides of binding sites exert independent effects on binding affinity. Our results stress the importance of complete reference tables of all possible binding sites for comparing protein binding preferences for various DNA sequences. We also show results suggesting that microarray binding data using particular subsets of all possible binding sites can be used to extrapolate the relative binding affinities of all possible full-length binding sites, given a known binding site for use as a starting sequence for site preference refinement.
* To whom correspondence should be addressed at: Harvard Medical School Department of Genetics, Alpert Building 514, 200 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 617 432 7562; Fax: +1 617 432 7266; Email: church{at}arep.med.harvard.edu Present address: Martha L. Bulyk, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Thorn Building 1014, 20 Shattuck Street, Boston, MA 02115, USA
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