Year: 2012
Type: article
Abstract: 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 cis–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 protein–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. DNase I footprinting in 41 cell and tissue types reveals millions of short sequence elements encoding an expansive repertoire of conserved recognition sequences for DNA-binding proteins. DNaseI footprinting detects DNA sequences that are protected from cleavage by DNaseI because they are bound by regulatory factors. Studying these footprints in 41 diverse cell and tissue types, the authors describe millions of short sequence elements that are conserved recognition sequences for DNA-binding proteins. The effort nearly doubles the size of the human cis-regulatory lexicon and provides insight into chromatin states and levels of evolutionary conservation. A large collection of novel regulatory-factor recognition motifs that closely parallel major regulators of development, differentiation and pluripotency is also described.
Source: Nature
DOI: 10.1038/nature11212
Authors: 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 Dunn, Jun 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
Institutions: University of Washington, Fred Hutch Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: A Comprehensive catalog of human DNasel hypersensitive sites, Digital DNaseI mapping and footprinting of the mouse genome, Function of human & mouse Beta-globin locus control regions, Inter-individual epigenetic variation in hematopoietic progenitor cells, G7755277651, G7999895773, Cancer Center Support Grant
OpenAlex ID: W2008051478