Repurposing of promoters and enhancers during mammalian evolution
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PROVIDER: PRJNA470431 | ENA |
REPOSITORIES: ENA
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Project description:The spatiotemporal control of gene expression exerted by promoters and enhancers is central for organismal development, physiology and behaviour. These two types of regulatory elements have long been distinguished from each other based on their function, but recent work highlighted common architectural and functional features. It also suggested that inheritable alterations in the epigenetic and sequence context of regulatory elements might underlie evolutionary changes of their principal activity, which could result in changes in the transcriptional profile of genes under their control or even facilitate the birth of new genes. Here, based on integrated cross-mammalian analyses of DNase hypersensitivity, chromatin modification and transcriptional data, we provide support for this hypothesis by detecting 445 regulatory elements with signatures of activity turnover in sister species from the primate and rodent lineages (termed "P/E" elements). Through the comparison with outgroup species, we defined the directionality of turnover events, which revealed that most instances represent transformations of putative ancestral enhancers into promoters, leading to the emergence of species-specific transcribed loci or 5' exons. Notably, P/E elements have distinct GC sequence compositions and stabilizing 5' splicing (U1) regulatory motif patterns, which may predispose them to functional repurposing during evolution. Moreover, we trace changes in the U1 and polyadenylation signal densities and distributions that accompanied and likely drove the evolutionary activity switches. Overall, our work highlights functional repurposing as a notable mechanism that likely facilitated regulatory innovation and the origination of new genes and exons during mammalian evolution.
2018-10-01 | GSE114191 | GEO
Project description: Not available
| S-EPMC6172195 | biostudies-literature
Project description: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 useful models for the study of new gene origination. Here we combine extensive 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, the majority 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, as well as from CpG islands not associated to other genes. Altogether, these mechanisms facilitated the birth of up to 280 retrogenes in each therian species. Furthermore, the regulatory evolution of the originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated the cooption of distant promoters and in many cases allowed the 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 their parents during the process of male (meiotic) X inactivation, while others even rendered parental functions completely superfluous, allowing for parental gene loss. Overall, our reconstruction of the complete â??life historyâ?? of mammalian retrogenes highlights the usefulness of retroposition as a general model for understanding new gene birth and functional evolution. Assembly and expression of vertebrate retrogene transcripts
2015-12-16 | E-GEOD-72236 | biostudies-arrayexpress
Project description: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 useful models for the study of new gene origination. Here we combine extensive 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, the majority 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, as well as from CpG islands not associated to other genes. Altogether, these mechanisms facilitated the birth of up to 280 retrogenes in each therian species. Furthermore, the regulatory evolution of the originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated the cooption of distant promoters and in many cases allowed the 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 their parents during the process of male (meiotic) X inactivation, while others even rendered parental functions completely superfluous, allowing for parental gene loss. Overall, our reconstruction of the complete “life history” of mammalian retrogenes highlights the usefulness of retroposition as a general model for understanding new gene birth and functional evolution.
2015-12-16 | GSE72236 | GEO
Project description:Extensive Functional Redundancy of Mammalian Enhancers
| PRJNA362215 | ENA
Project description:Evolution of mammalian miRNA genes
| PRJNA174234 | ENA
Project description:Anti-sense transcription originating upstream of mammalian protein-coding genes is a well-documented phenomenon, but remarkably little is known about the function or regulation of these anti-sense promoters or the non-coding RNAs they generate. Here we define at nucleotide resolution the divergent transcription start sites (TSSs) near mouse mRNAs. We find that coupled sense and anti-sense TSSs form the boundaries of an evolutionarily conserved and nucleosome-depleted regulatory region with dramatically enriched transcription factor (TF) occupancy. Notably, as the distance between sense and anti-sense TSSs increases, so does the level of TF binding and signal-dependent gene activation. We further discover a cluster of anti-sense TSSs in macrophages with an enhancer-like chromatin signature. Remarkably, this signature identifies promoters that are selectively and rapidly activated during immune challenge. We conclude that anti-sense TSSs can serve as potent, local enhancers of sense-strand gene expression by facilitating TF binding and deposition of activating histone modifications.
2015-06-23 | GSE62151 | GEO
Project description:Enhancers act to regulate cell type specific gene expression by facilitating the transcription of target genes. In mammalian cells active or primed enhancers are commonly marked by monomethylation of Histone H3 at lysine 4 (H3K4me1) in a cell-type specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals has been unclear. In the present study, we conducted SILAC Mass-spec experiments with mono-nucleosomes and identified multiple H3K4me1 associated proteins, including proteins involved in chromatin remodeling. We demonstrate that H3K4me1 augments the association of the chromatin remodeling complex BAF to enhancers in vivo. Furthermore we show that in vitro, H3K4me1 nucleosomes are more efficiently remodeled by the BAF complex. Crystal structures of a BAF component BAF45c further reveal that monomethylation, but not trimethylation, is accommodated in this protein’s H3K4 binding site. Our results suggest that H3K4me1 plays an active role at enhancers by facilitating the binding of the BAF complex and possibly other chromatin regulators.
2018-10-23 | PXD007942 | Pride
Project description:MicroRNAs (miRNAs) are major post-transcriptional regulators of gene expression, yet their origins and functional evolution in mammals remain little understood due to the lack of appropriate comparative data. Using RNA sequencing, we have generated extensive and comparable miRNA data for five organs in six species that represent all main mammalian lineages and birds (the evolutionary outgroup), with the aim to unravel the evolution of mammalian miRNAs. Our analyses reveal an overall expansion of miRNA repertoires in mammals, with three-fold accelerated birth rates of miRNA families in placentals and marsupials, facilitated by the de novo emergence of miRNAs in host gene introns. Generally, our analyses suggest a high rate of miRNA family turnover in mammals, with many newly emerged miRNA families being lost soon after their formation. Selectively preserved mammalian miRNA families gradually evolved higher expression levels as well as altered mature sequences and target gene repertoires, and were apparently mainly recruited to exert regulatory functions in nervous tissues. However, miRNAs that originated on the X chromosome evolved high expression levels and potentially diverse functions during spermatogenesis, including meiosis, through selectively driven duplication-divergence processes. Overall, our study thus provides detailed insights into the birth and evolution of mammalian miRNA genes and the associated selective forces. 30 main samples from five adult tissues (brain, cerebellum, heart, kidney and testis) collected in six species (human, macaque, mouse, opossum, platypus and chicken) + 5 biological replicates + 3 samples from spermatogenic cells in adult mouse testis (Sertoli cells, spermatocytes and spermatids)
2012-10-01 | E-GEOD-40499 | biostudies-arrayexpress
Project description:Gene expression in mammals is precisely regulated by combination of promoters and gene-distal regulatory regions, known as enhancers. Several studies have suggested that some promoters might play enhancer functions. However, the extent of this type of promoters and whether they actually function to regulate the expression of distal genes have remained elusive. Here, by exploiting a high-throughput enhancer reporter assay, we unravel a set of mammalian promoters displaying enhancer activity. These promoters have distinct genomic and epigenomic features and frequently interact with other gene-promoters. Extensive CRISPR/Cas9 genomic manipulation demonstrated their involvement in cis-regulation of distal gene expression in their natural loci. Our results have important implications for the understanding of complex gene regulation in normal development and disease.
2017-04-21 | GSE83296 | GEO