Conservation of trans-acting circuitry during mammalian regulatory evolution

Andrew B. Stergachis, Shane Neph, Richard Sandstrom, Eric Haugen, Alex P. Reynolds, Miaohua Zhang, Rachel Byron, Theresa Canfield, Sandra Stelhing-Sun, Kristen Lee, Robert E. Thurman, Shinny Vong, Daniel Bates, Fidencio Neri, Morgan Diegel, Erika Giste, Douglas Dunn, Jeff Vierstra, R. Scott Hansen, Audra K. Johnson, Peter J. Sabo, Matthew S. Wilken, Thomas A. Reh, Piper M. Treuting, Rajinder Kaul, Mark Groudine, M. A. Bender, Elhanan Borenstein and John A. Stamatoyannopoulos ()
Additional contact information
Andrew B. Stergachis: University of Washington
Shane Neph: University of Washington
Richard Sandstrom: University of Washington
Eric Haugen: University of Washington
Alex P. Reynolds: University of Washington
Miaohua Zhang: Fred Hutchinson Cancer Research Center
Rachel Byron: Fred Hutchinson Cancer Research Center
Theresa Canfield: University of Washington
Sandra Stelhing-Sun: University of Washington
Kristen Lee: University of Washington
Robert E. Thurman: University of Washington
Shinny Vong: University of Washington
Daniel Bates: University of Washington
Fidencio Neri: University of Washington
Morgan Diegel: University of Washington
Erika Giste: University of Washington
Douglas Dunn: University of Washington
Jeff Vierstra: University of Washington
R. Scott Hansen: University of Washington
Audra K. Johnson: University of Washington
Peter J. Sabo: University of Washington
Matthew S. Wilken: University of Washington
Thomas A. Reh: University of Washington
Piper M. Treuting: University of Washington
Rajinder Kaul: University of Washington
Mark Groudine: Fred Hutchinson Cancer Research Center
M. A. Bender: Fred Hutchinson Cancer Research Center
Elhanan Borenstein: University of Washington
John A. Stamatoyannopoulos: University of Washington

Nature, 2014, vol. 515, issue 7527, 365-370

Abstract: Abstract The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.

Date: 2014
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DOI: 10.1038/nature13972

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