An expansive human regulatory lexicon encoded in transcription factor footprints.

Nature 2012 Sep;489(7414):83-90

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

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.

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September 2012
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References

(Supplied by CrossRef)

DJ Galas et al.
Nucleic Acids Res. 1978

WS Dynan et al.
Cell 1983

DS Gross et al.
Annu. Rev. Biochem. 1988

JR Hesselberth et al.
Nature Methods 2009

D Thanos et al.
Cell 1995

SF Tsai et al.
Nature 1989

PJ Sabo et al.
Proc. Natl Acad. Sci. USA 2004

AP Boyle et al.
Cell 2008

V Matys et al.
Nucleic Acids Res. 2006

JC Bryne et al.
Nucleic Acids Res. 2008

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