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 et al.

Nature 515, 365–370 (20 November 2014) doi:10.1038/nature13972
Received 21 February 2014 Accepted 15 October 2014 Published online 19 November 2014

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.