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. 2018 Oct 4;9(1):4066.
doi: 10.1038/s41467-018-06544-z.

Repurposing of promoters and enhancers during mammalian evolution

Francesco N Carelli  1   2 , Angélica Liechti  3 , Jean Halbert  3 , Maria Warnefors  4 , Henrik Kaessmann  5
Affiliations

Repurposing of promoters and enhancers during mammalian evolution

Francesco N Carelli et al. Nat Commun. .

Abstract

Promoters and enhancers-key controllers of gene expression-have long been distinguished from each other based on their function. However, recent work suggested that common architectural and functional features might have facilitated the conversion of one type of element into the other during evolution. Here, based on cross-mammalian analyses of epigenome and transcriptome data, we provide support for this hypothesis by detecting 445 regulatory elements with signatures of activity turnover (termed P/E elements). Most events represent transformations of putative ancestral enhancers into promoters, leading to the emergence of species-specific transcribed loci or 5' exons. Distinct GC sequence compositions and stabilizing 5' splicing (U1) regulatory motif patterns may have predisposed P/E elements to regulatory repurposing, and changes in the U1 and polyadenylation signal densities and distributions likely drove the evolutionary activity switches. Our work suggests that regulatory repurposing facilitated regulatory innovation and the origination of new genes and exons during evolution.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Repurposing of regulatory elements in mammals. a Schematic representation of a P/E element in primates and rodents. b Types of P/E elements. c Total number of novel and extended P/E elements detected in primates and rodents. d Macaque and rat H3K4me3 ChIP-seq reads density from liver (log2 read count normalized by input read count) measured at novel and extended liver P/E elements, loci orthologous to the sister species liver enhancers and not associated to any stable TSS, and stable liver promoters conserved in the sister species. Whiskers up to 1.5 times the interquartile range; outliers removed for graphical purposes. Significant differences (Mann–Whitney U-test with Benjamini-Hochberg correction): ∗∗∗P < 0.001. e Fold- difference between P/E elements ratio (fraction of human or mouse enhancers corresponding to promoters in sister species) and P/inactive ratio (fraction of human or mouse inactive regions corresponding to promoters). The red line indicates no difference between the two ratios. Numbers indicate the number of P/E elements for each group. Significant differences (Fisher’s exact test with Benjamini-Hochberg correction): ∗∗∗P < 0.001
Fig. 2
Fig. 2
Repurposing of an ancestral glires enhancer. a The coordinates of a rodent P/E element, with enhancers activity in mouse and promoter activity in rat, are projected onto the rabbit genome (orange shaded area). The syntenic region in rabbit overlaps an H3K27ac peak but no H3K4me3 peak. The presence of a transcript in rat and absence of transcripts in mouse and rabbit are evident based on the RNA-seq tracks. For each species (from top to bottom) are shown: the RNA-seq coverage from liver; the assembled transcripts (only in rat); the P/E element locus; the liver H3K4me3 and H3K27Ac coverage and peaks from Villar et al. (2015). b Scheme depicting the different types of turnover events (Regulatory repurposing vs evolutionary loss) for ancestral enhancers and promoters
Fig. 3
Fig. 3
Nucleotide composition of P/E elements. a–d Distribution of GC and CpG content for different classes of regulatory elements in human and mouse. Whiskers up to 1.5 times the interquartile range; outliers removed for graphical purposes. Significant differences (Mann–Whitney U-test with Benjamini-Hochberg correction): ∗∗∗P < 0.001; ∗∗P < 0.01; ∗P < 0.05; (n.s.) P ≥ 0.05. e Distribution of CpG dinucleotide frequency in orthologous rodent P/E elements. Whiskers up to 1.5 times the interquartile range. f CpG frequency difference measured between orthologous inactive regions. The distribution was obtained by resampling 10,000 times a number of orthologous inactive regions equal to the number of P/E elements in d and calculating the average CpG frequency difference. The red line indicates the mean CpG frequency difference between orthologous rodent P/E elements. The P-value indicates the fraction of resampled inactive regions with an average CpG frequency higher than that of P/E elements ∗∗∗P < 0.001)
Fig. 4
Fig. 4
U1 site distribution at P/E elements. a Schematic representation of an orthologous P/E element. The orange line depicts the position of the TSS in rat and of the projected location in mouse. b, c Distribution of U1 site density per kb upstream (dashed line) and downstream (continuous line) of the TSS of transcripts associated to novel P/E elements in rat b and mouse c. Significant differences (Mann–Whitney U-test with Benjamini-Hochberg correction): ∗∗∗P < 0.001; ∗P < 0.05. d, e Cumulative density of U1 sites up- and downstream of novel P/E-associated TSSs in rodents and primates, respectively. Lines represent the mean U1 density (per kb) over 200, 400, 600, 800, and 1000 nt-long windows from the TSS, shaded areas represent 95% confidence intervals. Significant differences (Mann–Whitney U-test with Benjamini-Hochberg correction): ∗∗∗P < 0.001; ∗∗P < 0.01; (n.s.) P ≥ 0.05. f Distribution of up- and downstream distances of the closest U1 site from each novel P/E-associated TSS in rodents. Whiskers up to 1.5 times the interquartile range; outliers removed for graphical purposes. Significant differences (one-tailed Mann–Whitney U-test with Benjamini-Hochberg correction): ∗∗P < 0.01; (n.s.) P ≥ 0.05
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