Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

Berthelot, Camille; Villar, Diego; Horvath, Julie E.; Odom, Duncan T.; Flicek, Paul

doi:10.1038/s41559-017-0377-2

Cited by 133 publications

(161 citation statements)

References 82 publications

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“…6b) and the number of loop interactions with distal sites. These observations are also compatible with those made very recently in liver tissue 47 . In addition, we find a strong correlation in the opposite direction at the distal end of loops, where promoters that form more loop interactions have enhancers that are less, rather than more, conserved at the level of both transcription (Fig.…”

Section: Discussionsupporting

confidence: 93%

Dynamic evolution of regulatory element ensembles in primate CD4+ T cells

et al. 2018

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How evolutionary changes at enhancers affect the transcription of target genes remains an important open question. Previous comparative studies of gene expression have largely measured the abundance of mRNA, which is affected by post-transcriptional regulatory processes, hence limiting inferences about the mechanisms underlying expression differences. Here we directly measured nascent transcription in primate species, allowing us to separate transcription from post-transcriptional regulation. We used PRO-seq to map RNA polymerases in resting and activated CD4+ T-cells in multiple human, chimpanzee, and rhesus macaque individuals, with rodents as outgroups. We observed general conservation in coding and non-coding transcription, punctuated by numerous differences between species, particularly at distal enhancers and non-coding RNAs. Genes regulated by larger numbers of enhancers are more frequently transcribed at evolutionarily stable levels, despite reduced conservation at individual enhancers. Adaptive nucleotide substitutions are associated with lineage-specific transcription, and at one locus, SGPP2, we predict and experimentally validate that multiple substitutions contribute to human-specific transcription. Collectively, our findings suggest a pervasive role for evolutionary compensation across ensembles of enhancers that jointly regulate target genes.

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Section: Discussionsupporting

confidence: 93%

Dynamic evolution of regulatory element ensembles in primate CD4+ T cells

et al. 2018

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“…The relative importance of conserved and novel enhancers remains an open question that is of significant interest to the field. It has been suggested that recently evolved enhancers have a somewhat smaller effect on gene expression than shared/conserved elements and have a slight association with genes showing evolutionarily stable expression levels (Berthelot et al 2018). It also remains unclear the degree to which selection pressures have driven convergent, functional sequence changes such as in transcription factor binding sites in TWARs.…”

Section: Discussionmentioning

confidence: 99%

Widespread cis-regulatory convergence between the extinct Tasmanian tiger and gray wolf

2019

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The extinct marsupial Tasmanian tiger, or thylacine, and the eutherian gray wolf are among the most widely recognized examples of convergent evolution in mammals. Despite being distantly related, these large predators independently evolved extremely similar craniofacial morphologies, and evidence suggests that they filled similar ecological niches. Previous analyses revealed little evidence of adaptive convergence between their protein-coding genes. Thus, the genetic basis of their convergence is still unclear. Here, we identified candidate craniofacial cis-regulatory elements across vertebrates and compared their evolutionary rates in the thylacine and wolf, revealing abundant signatures of convergent positive selection. Craniofacial thylacine-wolf accelerated regions were enriched near genes involved in TGF beta (TGFB) and BMP signaling, both of which are key morphological signaling pathways with critical roles in establishing the identities and boundaries between craniofacial tissues. Similarly, enhancers of genes involved in craniofacial nerve development showed convergent selection and involvement in these pathways. Taken together, these results suggest that adaptation in cis-regulators of TGF beta and BMP signaling may provide a mechanism to explain the coevolution of developmentally and functionally integrated craniofacial structures in these species. We also found that despite major structural differences in marsupial and eutherian brains, accelerated regions in both species were common near genes with roles in brain development. Our findings support the hypothesis that, relative to protein-coding genes, positive selection on cis-regulatory elements is likely to be an essential driver of adaptive convergent evolution and may underpin thylacine-wolf phenotypic similarities.

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“…Over the recent years, since more systematic perturbative experiments of candidate non-coding sequences have become possible, we have learned that mammalian regulatory landscapes are extremely complex and often contain redundant enhancers and that the impact of individual putative enhancer deletion/silencing on expression of target genes is dependent on inherent enhancer strength, number and strength of other active enhancers acting on the same gene in a given cell type, and spatial constraints reflected in the frequency of contact with the target promoter(s) [59][60][61][62][63]. Furthermore, while relationships among enhancers within a regulatory landscape are often additive [64], examples of other relationships, including synergistic, competitive and hierarchical, have been described in the literature (reviewed in [42]). We should expect that TE-derived enhancers will participate in these complex relationships and thus their activity (or lack thereof ) should be interpreted in a broader context of a given regulatory landscape.…”

Section: Transcription Of Merv-l/herv-h Elements Establishes Cell-typmentioning

confidence: 99%

Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

Sundaram

Wysocka

2020

Phil. Trans. R. Soc. B

165

153

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Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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Complexity and conservation of regulatory landscapes underlie evolutionary resilience of mammalian gene expression

Cited by 133 publications

References 82 publications

Dynamic evolution of regulatory element ensembles in primate CD4+ T cells

Dynamic evolution of regulatory element ensembles in primate CD4+ T cells

Widespread cis-regulatory convergence between the extinct Tasmanian tiger and gray wolf

Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

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