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Transcription Factor Binding: Does Order Matter?

Gabriel Kreiman & Nambi Nallasamy

Gene expression in eukaryotes is orchestrated by the binding of transcription factors (TFs) to cis regulatory elements in the DNA [1-3].  Regulatory regions in eukaryotes show a hierarchical structure of separate modules with multiple TF binding sites within each module.  In many cases, the position, order and orientation of separate modules can be changed considerably without affecting transcriptional rate.  However, the detailed internal structure within modules is only poorly understood.

Here we asked whether the order of TF binding sites within a module matters or not.  We studied the relative orientation and order for all possible pairs from a large collection of yeast and mammalian TF binding sites.  Throughout non-coding regions upstream of genes, we observed a large number of examples where one particular ordering was much more prevalent than the reverse order.

Our observations suggest that the internal structure of regulatory modules, in particular the spatial order of TF binding to DNA, may play an important role in the specificity of gene expression control.  Further understanding the structure of transcriptional control regions could help improve current algorithms to detect regulatory elements [2].


This report describes research done at the Center for Biological & Computational Learning, which is in the McGovern Institute for Brain Research at MIT, as well as in the Dept. of Brain & Cognitive Sciences, and which is affiliated with the Computer Sciences & Artificial Intelligence Laboratory (CSAIL).

This research was sponsored by grants from: Office of Naval Research (DARPA) Contract No. MDA972-04-1-0037, Office of Naval Research (DARPA) Contract No. N00014-02-1-0915, National Science Foundation (ITR/SYS) Contract No. IIS-0112991, National Science Foundation (ITR) Contract No. IIS-0209289, National Science Foundation-NIH (CRCNS) Contract No. EIA-0218693, National Science Foundation-NIH (CRCNS) Contract No. EIA-0218506, and National Institutes of Health (Conte) Contract No. 1 P20 MH66239-01A1.

Additional support was provided by: Central Research Institute of Electric Power Industry (CRIEPI), Daimler-Chrysler AG, Compaq/Digital Equipment Corporation, Eastman Kodak Company, Honda R&D Co., Ltd., Industrial Technology Research Institute (ITRI), Komatsu Ltd., Eugene McDermott Foundation, Merrill-Lynch, NEC Fund, Oxygen, Siemens Corporate Research, Inc., Sony, Sumitomo Metal Industries, and Toyota Motor Corporation.


[1] Davidson, E. et al. (2002). “A Genomic Regulatory Network for Development,” Science, 295, 1669-1678.

[2] Kreiman, G. (2004). “Identification of Sparsely Distributed Clusters of Cis-regulatory Elements in Sets of Co-expressed Genes,”Nucl. Acids Res,. 32, 2889-2900.

[3] Ohler, U., and Frith, M. (2005).  “Models for Complex Eukaryotic Regulatory DNA Sequences. (in press).

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