A unified architecture of transcriptional regulatory elements

Andersson, Robin; Sandelin, Albin; Danko, Charles G.

doi:10.1016/j.tig.2015.05.007

Cited by 185 publications

(184 citation statements)

References 83 publications

(136 reference statements)

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“…Moreover, at least 8%-9% of expressed retrocopies apparently recruited nearby regulatory elements, which function as enhancers in outgroup species, as promoters. This observation is consistent with recent work highlighting common functional and structural features shared by enhancers and promoters Andersson et al 2015). It also suggests that enhancers and promoters may evolve from the same ancestral regulatory elements and/or that enhancers may "metamorphose" into promoters.…”

Section: Discussionsupporting

confidence: 91%

“…We next explored to what extent retrocopy promoters may have been derived from other proto-promoters (sequences displaying promoter-like characteristics prior to retrocopy insertion). It has recently become apparent that enhancers and promoters share many key properties Andersson et al 2015). We therefore speculated that enhancers, or enhancer-like elements (see Discussion), might have been co-opted as retrocopy promoters during evolution.…”

Section: Retrocopies With Active Promotersmentioning

confidence: 96%

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The life history of retrocopies illuminates the evolution of new mammalian genes

et al. 2016

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New genes contribute substantially to adaptive evolutionary innovation, but the functional evolution of new mammalian genes has been little explored at a broad scale. Previous work established mRNA-derived gene duplicates, known as retrocopies, as models for the study of new gene origination. Here we combine mammalian transcriptomic and epigenomic data to unveil the processes underlying the evolution of stripped-down retrocopies into complex new genes. We show that although some robustly expressed retrocopies are transcribed from preexisting promoters, most evolved new promoters from scratch or recruited proto-promoters in their genomic vicinity. In particular, many retrocopy promoters emerged from ancestral enhancers (or bivalent regulatory elements) or are located in CpG islands not associated with other genes. We detected 88–280 selectively preserved retrocopies per mammalian species, illustrating that these mechanisms facilitated the birth of many functional retrogenes during mammalian evolution. The regulatory evolution of originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated co-option of distant promoters and allowed expression of alternative isoforms. While young retrogenes are often initially expressed in the testis, increased regulatory and structural complexities allowed retrogenes to functionally diversify and evolve somatic organ functions, sometimes as complex as those of their parents. Thus, some retrogenes evolved the capacity to temporarily substitute for their parents during the process of male meiotic X inactivation, while others rendered parental functions superfluous, allowing for parental gene loss. Overall, our reconstruction of the “life history” of mammalian retrogenes highlights retroposition as a general model for understanding new gene birth and functional evolution.

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Section: Discussionsupporting

confidence: 91%

Section: Retrocopies With Active Promotersmentioning

confidence: 96%

The life history of retrocopies illuminates the evolution of new mammalian genes

et al. 2016

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“…Both positive and negative relationships between enhancer and promoter activities have been recently hypothesized (Kim et al 2010;Li et al 2012;Andersson et al 2015), so we compared the enhancer and promoter activities of defined sequences. We observe a clear positive correlation between enhancer and promoter activity (Spearman's ρ = 0.45 and P < 10…”

Section: Resultsmentioning

confidence: 99%

“…Conversely, gene and lncRNA promoter sequences also encode enhancer activity (Webster et al 1988;Li et al 2012;Zabidi et al 2015;Paralkar et al 2016); although, the frequency at which this occurs outside of Drosophila is unknown. These findings suggest that within metazoan genomes, sequences that encode enhancer and promoter activities may be overlapping or even identical (WeingartenGabbay and Segal 2014; Andersson et al 2015;Kim and Shiekhattar 2015;Li et al 2016). However, because the promoter and enhancer activities of only a few defined sequences have been directly compared (Moreau et al 1981;Serfling et al 1985;Treisman and Maniatis 1985;Bienz and Pelham 1986), the fundamental relationships between enhancer activity, promoter activity, and the sequences that encode them are unknown.…”

mentioning

confidence: 99%

High-throughput functional comparison of promoter and enhancer activities

et al. 2016

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Promoters initiate RNA synthesis, and enhancers stimulate promoter activity. Whether promoter and enhancer activities are encoded distinctly in DNA sequences is unknown. We measured the enhancer and promoter activities of thousands of DNA fragments transduced into mouse neurons. We focused on genomic loci bound by the neuronal activity-regulated coactivator CREBBP, and we measured enhancer and promoter activities both before and after neuronal activation. We find that the same sequences typically encode both enhancer and promoter activities. However, gene promoters generate more promoter activity than distal enhancers, despite generating similar enhancer activity. Surprisingly, the greater promoter activity of gene promoters is not due to conventional core promoter elements or splicing signals. Instead, we find that particular transcription factor binding motifs are intrinsically biased toward the generation of promoter activity, whereas others are not. Although the specific biases we observe may be dependent on experimental or cellular context, our results suggest that gene promoters are distinguished from distal enhancers by specific complements of transcriptional activators.

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“…Transcribed enhancers have some promoter-like motifs, including the INR motif, leading to the proposal of a "unified architecture" between enhancer and promoter sequences (Core et al 2014;Andersson et al 2015). However, promoters differ strongly from enhancers in their ability to be activated by enhancers (enhancer responsiveness) (Arnold et al 2017) and to regulate spatial activity.…”

Section: Highly Transcribed Developmental Enhancers Have Weak Promotementioning

confidence: 99%

The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription

et al. 2018

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Gene expression is regulated by promoters, which initiate transcription, and enhancers, which control their temporal and spatial activity. However, the discovery that mammalian enhancers also initiate transcription questions the inherent differences between enhancers and promoters. Here, we investigate the transcriptional properties of enhancers during Drosophila embryogenesis using characterized developmental enhancers. We show that while the timing of enhancer transcription is generally correlated with enhancer activity, the levels and directionality of transcription are highly varied among active enhancers. To assess how this impacts function, we developed a dual transgenic assay to simultaneously measure enhancer and promoter activities from a single element in the same embryo. Extensive transgenic analysis revealed a relationship between the direction of endogenous transcription and the ability to function as an enhancer or promoter in vivo, although enhancer RNA (eRNA) production and activity are not always strictly coupled. Some enhancers (mainly bidirectional) can act as weak promoters, producing overlapping spatio-temporal expression. Conversely, bidirectional promoters often act as strong enhancers, while unidirectional promoters generally cannot. The balance between enhancer and promoter activity is generally reflected in the levels and directionality of eRNA transcription and is likely an inherent sequence property of the elements themselves.

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A unified architecture of transcriptional regulatory elements

Cited by 185 publications

References 83 publications

The life history of retrocopies illuminates the evolution of new mammalian genes

The life history of retrocopies illuminates the evolution of new mammalian genes

High-throughput functional comparison of promoter and enhancer activities

The degree of enhancer or promoter activity is reflected by the levels and directionality of eRNA transcription

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