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Nature. 2014 Nov 20;515(7527):365-70. doi: 10.1038/nature13972.

Conservation of trans-acting circuitry during mammalian regulatory evolution.

Author information

1
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
2
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
3
1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
4
Department of Biological Structure, University of Washington, Seattle, Washington 98195, USA.
5
Department of Comparative Medicine, University of Washington, Seattle, Washington 98195, USA.
6
1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Division of Radiation Oncology, University of Washington, Seattle, Washington 98195, USA.
7
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA [2] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA.
8
1] Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA [2] Department of Computer Science and Engineering, University of Washington, Seattle, Washington 98102, USA [3] Santa Fe Institute, Santa Fe, New Mexico 87501, USA.

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.

PMID:
25409825
PMCID:
PMC4405208
DOI:
10.1038/nature13972
[Indexed for MEDLINE]
Free PMC Article

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