Enhancer Evolution Across 20 Mammalian Species

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Jan 31

PMID 25635462

Citations 394

Authors

Diego Villar

Camille Berthelot

Sarah Aldridge

Tim F Rayner

Margus Lukk

Miguel Pignatelli

Thomas J Park

Robert Deaville

Jonathan T Erichsen

Anna J Jasinska

James M A Turner

Mads F Bertelsen

Elizabeth P Murchison

Paul Flicek

Duncan T Odom

Affiliations

Soon will be listed here.

Abstract

The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.

Citing Articles

The combinatorial binding syntax of transcription factors in forebrain-specific enhancers.

Batool F, Shireen H, Malik M, Abrar M, Abbasi A Biol Open. 2025; 14(2).

PMID: 39976127 PMC: 11876843. DOI: 10.1242/bio.061751.

Sequence-based GWAS in 180,000 German Holstein cattle reveals new candidate variants for milk production traits.

Krizanac A, Reimer C, Heise J, Liu Z, Pryce J, Bennewitz J Genet Sel Evol. 2025; 57(1):3.

PMID: 39905301 PMC: 11796172. DOI: 10.1186/s12711-025-00951-9.

An Attention-Based Deep Neural Network Model to Detect Cis-Regulatory Elements at the Single-Cell Level From Multi-Omics Data.

Murakami K, Iida K, Okada M Genes Cells. 2025; 30(2):e70000.

PMID: 39904740 PMC: 11794194. DOI: 10.1111/gtc.70000.

Abundant repressor binding sites in human enhancers are associated with the fine-tuning of gene regulation.

Song W, Ovcharenko I iScience. 2025; 28(1):111658.

PMID: 39868043 PMC: 11761325. DOI: 10.1016/j.isci.2024.111658.

The emergence and evolution of gene expression in genome regions replete with regulatory motifs.

Fuqua T, Sun Y, Wagner A Elife. 2024; 13.

PMID: 39704646 PMC: 11661796. DOI: 10.7554/eLife.98654.

References

Buenrostro J, Giresi P, Zaba L, Chang H, Greenleaf W . Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013; 10(12):1213-8. PMC: 3959825. DOI: 10.1038/nmeth.2688. View

Nord A, Blow M, Attanasio C, Akiyama J, Holt A, Hosseini R . Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell. 2013; 155(7):1521-31. PMC: 3989111. DOI: 10.1016/j.cell.2013.11.033. View

Yim H, Cho Y, Guang X, Kang S, Jeong J, Cha S . Minke whale genome and aquatic adaptation in cetaceans. Nat Genet. 2013; 46(1):88-92. PMC: 4079537. DOI: 10.1038/ng.2835. View

Petryszak R, Burdett T, Fiorelli B, Fonseca N, Gonzalez-Porta M, Hastings E . Expression Atlas update--a database of gene and transcript expression from microarray- and sequencing-based functional genomics experiments. Nucleic Acids Res. 2013; 42(Database issue):D926-32. PMC: 3964963. DOI: 10.1093/nar/gkt1270. View

Flicek P, Amode M, Barrell D, Beal K, Billis K, Brent S . Ensembl 2014. Nucleic Acids Res. 2013; 42(Database issue):D749-55. PMC: 3964975. DOI: 10.1093/nar/gkt1196. View

Villar D, Flicek P, Odom D . Evolution of transcription factor binding in metazoans - mechanisms and functional implications. Nat Rev Genet. 2014; 15(4):221-33. PMC: 4175440. DOI: 10.1038/nrg3481. View

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M . An atlas of active enhancers across human cell types and tissues. Nature. 2014; 507(7493):455-461. PMC: 5215096. DOI: 10.1038/nature12787. View

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

Grant C, Bailey T, Noble W . FIMO: scanning for occurrences of a given motif. Bioinformatics. 2011; 27(7):1017-8. PMC: 3065696. DOI: 10.1093/bioinformatics/btr064. View

10.

Cain C, Blekhman R, Marioni J, Gilad Y . Gene expression differences among primates are associated with changes in a histone epigenetic modification. Genetics. 2011; 187(4):1225-34. PMC: 3070530. DOI: 10.1534/genetics.110.126177. View

11.

He Q, Bardet A, Patton B, Purvis J, Johnston J, Paulson A . High conservation of transcription factor binding and evidence for combinatorial regulation across six Drosophila species. Nat Genet. 2011; 43(5):414-20. DOI: 10.1038/ng.808. View

12.

Santos-Rosa H, Schneider R, Bannister A, Sherriff J, Bernstein B, Emre N . Active genes are tri-methylated at K4 of histone H3. Nature. 2002; 419(6905):407-11. DOI: 10.1038/nature01080. View

13.

Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S . Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004; 5(10):R80. PMC: 545600. DOI: 10.1186/gb-2004-5-10-r80. View

14.

Ludwig M, Palsson A, Alekseeva E, Bergman C, Nathan J, Kreitman M . Functional evolution of a cis-regulatory module. PLoS Biol. 2005; 3(4):e93. PMC: 1064851. DOI: 10.1371/journal.pbio.0030093. View

15.

Cooper G, Stone E, Asimenos G, Green E, Batzoglou S, Sidow A . Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005; 15(7):901-13. PMC: 1172034. DOI: 10.1101/gr.3577405. View

16.

Frith M, Ponjavic J, Fredman D, Kai C, Kawai J, Carninci P . Evolutionary turnover of mammalian transcription start sites. Genome Res. 2006; 16(6):713-22. PMC: 1473182. DOI: 10.1101/gr.5031006. View

17.

Prabhakar S, Poulin F, Shoukry M, Afzal V, Rubin E, Couronne O . Close sequence comparisons are sufficient to identify human cis-regulatory elements. Genome Res. 2006; 16(7):855-63. PMC: 1484452. DOI: 10.1101/gr.4717506. View

18.

Pollard K, Salama S, Lambert N, Lambot M, Coppens S, Pedersen J . An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 2006; 443(7108):167-72. DOI: 10.1038/nature05113. View

19.

Mortazavi A, Leeper Thompson E, Garcia S, Myers R, Wold B . Comparative genomics modeling of the NRSF/REST repressor network: from single conserved sites to genome-wide repertoire. Genome Res. 2006; 16(10):1208-21. PMC: 1581430. DOI: 10.1101/gr.4997306. View

20.

Pennacchio L, Ahituv N, Moses A, Prabhakar S, Nobrega M, Shoukry M . In vivo enhancer analysis of human conserved non-coding sequences. Nature. 2006; 444(7118):499-502. DOI: 10.1038/nature05295. View