Conservation of trans-acting circuitry during mammalian regulatory evolution
Open accessAbstract
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. Mouse genomic footprinting reveals conservation of transcription factor (TF) recognition repertoires and trans-regulatory circuitry despite massive turnover of DNA elements that contact TFs in vivo. Having generated genomic DNase I footprinting data of the mouse genome across 25 cell and tissue types, these authors use these data to quantify cis-versus-trans regulatory contributions to mammalian regulatory evolution. They describe more than 600 motifs that collectively are over 95% similar to that recognized in vivo by human transcription factors (TFs). Despite substantial turnover of the cis-regulatory landscape around each TF gene, 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. Conservation between mouse and human TF regulatory networks is particularly similar at the highest organization level. The work was performed as part of the mouse ENCODE project.
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Nearly half of all pairwise regulatory interactions connecting mouse transcription factor genes have been maintained in orthologous human tissues, including brain.
“Moreover, studies indicate that nearly half of all pairwise regulatory interactions connecting mouse transcription factor genes have been maintained in orthologous human tissues, including brain (Ravasi et al., 2010; Stergachis et al., 2014).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Stergachis et al., 2014
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- Authors
- Stergachis, A. B., Neph, S., Sandstrom, R., Haugen, E., Reynolds, A. P., Zhang, M., Byron, R., Canfield, T., Stelhing-Sun, S., Lee, K., Thurman, R. E., Vong, S., Bates, D., Neri, F., Diegel, M., Giste, E., Dunn, D., Vierstra, J., Hansen, R. S., Johnson, A. K., Sabo, P. J., Wilken, M. S., Reh, T. A., Treuting, P. M., Kaul, R., Groudine, M., Bender, M. A., Borenstein, E., & Stamatoyannopoulos, J. A.
- Affiliations
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Santa Fe Institute (US)
- Corresponding author
- Stamatoyannopoulos, John A.
- ORCID
- Venue
- Nature
- Published
- 2014-11-19
- Volume
- 515
- Issue
- 7527
- Pages
- 365-370
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4405208
- OpenAlex
- W1987320425
- Cited by
- 212
- References
- 41
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 12 · 2023: 9 · 2022: 7 · 2021: 13 · 2020: 19 · 2019: 21 · 2018: 25 · 2017: 25 · 2016: 35 · 2015: 28 · 2014: 5
- FWCI
- 12.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (FDK095678A)
- National Human Genome Research Institute (U54HG004592, RC2HG005654, U54HG007010)
- National Eye Institute (R01EY021482)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK044746, F30DK095678, R37DK44746)
- National Institute of Environmental Health Sciences (U01ES01156)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- transcription factor binding sites, cis-regulatory elements, regulatory evolution, DNase I footprinting, mouse genome, human orthologs, transcriptional regulatory networks, ENCODE, mammalian gene regulation
- MeSH terms
- Animals, Humans, Mammals, Regulatory Sequences, Nucleic Acid, Transcription Factors, Conserved Sequence, Gene Expression Regulation, Developmental, DNA Footprinting, Evolution, Molecular, Mice, Gene Regulatory Networks
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