Conservation of mammalian trans-regulatory circuitry under high cis-regulatory turnover. A. B. Stergachis1, S. Neph1, R. Sandstrom1, E. Haugen1, A. Reynolds1, M. Zhang2, R. Byron2, T. Canfield1, S. Stelhing-Sun1, K. Lee1, R. Thurman1, S. Vong1, D. Bates1, F. Neri1, M. Diegel1, E. Giste1, D. Dunn1, S. Hansen1,2, A. Johnson1, P. Sabo1, M. Wilken3, T. Reh3, P. Treuting4, R. Kaul1,2, M. Groudine2,5, M. Bender5,6, E. Borenstein1, J. Stamatoyannopoulos1,2 1) Department of Genome Sciences, University of Washington, Seattle, WA, USA; 2) Department of Medicine, University of Washington, Seattle, WA USA; 3) Department of Biological Structure, University of Washington, Seattle, WA USA; 4) Department of Comparative Medicine, University of Washington, Seattle, WA, USA; 5) Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 6) Department of Pediatrics, University of Washington, Seattle, WA, USA.

   The anatomical body plan and its fundamental physiological axes have been highly conserved during the extended interval of mammalian evolution separating mice and humans, though only a fraction of the human genome evinces evolutionary constraint. To quantify cis- vs. trans-regulatory contributions to the evolution of mammalian regulatory programs, we performed extensive genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining 8.6 million TF occupancy sites on the mouse genome at nucleotide resolution. Here we show that mouse TF footprints encode a regulatory lexicon of 600 motifs that is 95% similar with those recognized in vivo by human TFs. However, only ~20% of mouse TF footprints have occupied human sequence orthologs. Despite substantial turnover of the cis-regulatory landscape around each TF gene, nearly half of the cross-regulatory connections between individual TF genes have been maintained in orthologous human cell types through innovated TF recognition sequences. Strikingly, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is substantially identical with human. Our results suggest that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry.

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