An expansive human regulatory lexicon encoded in transcription factor footprints

Shane Neph, Jeff Vierstra, Andrew B. Stergachis, Alex P. Reynolds, Eric Haugen, Benjamin Vernot, Robert E. Thurman, Sam John, Richard Sandstrom, Audra K. Johnson, Matthew T. Maurano, Richard Humbert, Eric Rynes, Hao Wang, Shinny Vong, Kristen Lee, Daniel Bates, Morgan Diegel, Vaughn Roach, Douglas DunnJun Neri, Anthony Schafer, R. Scott Hansen, Tanya Kutyavin, Erika Giste, Molly Weaver, Theresa Canfield, Peter Sabo, Miaohua Zhang, Gayathri Balasundaram, Rachel Byron, Michael J. MacCoss, Joshua M. Akey, M. A. Bender, Mark Groudine, Rajinder Kaul, John A. Stamatoyannopoulos

Research output: Contribution to journalArticlepeer-review

586 Scopus citations


Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cisĝ€"regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of proteinĝ€"DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
Issue number7414
StatePublished - Sep 6 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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