Publication Date:
2012-09-08
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736582/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736582/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neph, Shane -- Vierstra, Jeff -- Stergachis, Andrew B -- Reynolds, Alex P -- Haugen, Eric -- Vernot, Benjamin -- Thurman, Robert E -- John, Sam -- Sandstrom, Richard -- Johnson, Audra K -- Maurano, Matthew T -- Humbert, Richard -- Rynes, Eric -- Wang, Hao -- Vong, Shinny -- Lee, Kristen -- Bates, Daniel -- Diegel, Morgan -- Roach, Vaughn -- Dunn, Douglas -- Neri, Jun -- Schafer, Anthony -- Hansen, R Scott -- Kutyavin, Tanya -- Giste, Erika -- Weaver, Molly -- Canfield, Theresa -- Sabo, Peter -- Zhang, Miaohua -- Balasundaram, Gayathri -- Byron, Rachel -- MacCoss, Michael J -- Akey, Joshua M -- Bender, M A -- Groudine, Mark -- Kaul, Rajinder -- Stamatoyannopoulos, John A -- F30 DK095678/DK/NIDDK NIH HHS/ -- HG004592/HG/NHGRI NIH HHS/ -- P30 CA015704/CA/NCI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- RC2 HG005654/HG/NHGRI NIH HHS/ -- RC2HG005654/HG/NHGRI NIH HHS/ -- U54 HG004592/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):83-90. doi: 10.1038/nature11212.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955618" target="_blank"〉PubMed〈/a〉
Keywords:
DNA/*genetics
;
*DNA Footprinting
;
DNA Methylation
;
DNA-Binding Proteins/metabolism
;
Deoxyribonuclease I/metabolism
;
*Encyclopedias as Topic
;
Genome, Human/*genetics
;
Genomic Imprinting
;
Genomics
;
Humans
;
*Molecular Sequence Annotation
;
Polymorphism, Single Nucleotide/genetics
;
Regulatory Sequences, Nucleic Acid/*genetics
;
Transcription Factors/*metabolism
;
Transcription Initiation Site
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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