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Published online on April 18, 2007, 10.1073/pnas.0701811104 OPEN ACCESS ARTICLE


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Genetics
Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites

( comparative genomics | conserved noncoding element )

Xiaohui Xie {dagger}, Tarjei S. Mikkelsen {dagger}{ddagger}, Andreas Gnirke {dagger}, Kerstin Lindblad-Toh {dagger}, Manolis Kellis {dagger}{sect}, and Eric S. Lander {dagger}¶||{dagger}{dagger}

{dagger}Broad Institute of MIT and Harvard, Massachusetts Institute of Technology and Harvard Medical School, Cambridge, MA 02142; {ddagger}Division of Health Sciences and Technology, {sect}Computer Science and Artificial Intelligence Laboratory, and ||Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and Whitehead Institute for Biomedical Research, Cambridge, MA 02142

Contributed by Eric S. Lander, March 3, 2007 (sent for review January 26, 2007)

Conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, yet their function remains largely unknown. Experimental evidence suggests that many of these elements play regulatory roles, but little is known about regulatory motifs contained within them. Here we describe a systematic approach to discover and characterize regulatory motifs within mammalian CNEs by searching for long motifs (12-22 nt) with significant enrichment in CNEs and studying their biochemical and genomic properties. Our analysis identifies 233 long motifs (LMs), matching a total of {approx}60,000 conserved instances across the human genome. These motifs include 16 previously known regulatory elements, such as the histone 3'-UTR motif and the neuron-restrictive silencer element, as well as striking examples of novel functional elements. The most highly enriched motif (LM1) corresponds to the X-box motif known from yeast and nematode. We show that it is bound by the RFX1 protein and identify thousands of conserved motif instances, suggesting a broad role for the RFX family in gene regulation. A second group of motifs (LM2*) does not match any previously known motif. We demonstrate by biochemical and computational methods that it defines a binding site for the CTCF protein, which is involved in insulator function to limit the spread of gene activation. We identify nearly 15,000 conserved sites that likely serve as insulators, and we show that nearby genes separated by predicted CTCF sites show markedly reduced correlation in gene expression. These sites may thus partition the human genome into domains of expression.

Author contributions: X.X. and E.S.L. designed research; X.X. and E.S.L. performed research; X.X., T.S.M., A.G., K.L.-T., M.K., and E.S.L. contributed new reagents/analytic tools; X.X., T.S.M., A.G., K.L.-T., M.K., and E.S.L. analyzed data; and X.X., T.S.M., A.G., K.L.-T., M.K., and E.S.L. wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.

{dagger}{dagger}To whom correspondence should be addressed.

Eric S. Lander, E-mail: lander{at}broad.mit.edu

www.pnas.org/cgi/doi/10.1073/pnas.0701811104
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