Human gene regulatory evolution is driven by divergence in cis and trans
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens Macaca mulatta
PROVIDER: GSE216917 | GEO | 2023/12/22
REPOSITORIES: GEO
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Project description:Phenotypic differences between closely related species are thought to arise primarily from changes in gene expression due to mutations in cis-regulatory sequences (enhancers). However, it has remained unclear, how frequently mutations alter enhancer activity or create functional enhancers de novo. Here, we use STARR-seq, a recently developed quantitative enhancer assay, to determine genome-wide enhancer activity profiles for five Drosophila species in the constant trans-regulatory environment of D. melanogaster S2 cells. We find that the function of a large fraction of D. melanogaster enhancers is conserved in their orthologous sequences due to selection and stabilizing turnover of transcription factor motifs. Moreover, hundreds of enhancers have been gained since the D. melanogaster M-bM-^@M-^S D. yakuba split about 11 million years ago without apparent adaptive selection and can contribute to gene expression changes in vivo. Our finding that enhancer activity is often deeply conserved and frequently gained provides important functional insights into regulatory evolution. STARR-seq was performed in S2 cells with paired-end sequencing in two replicates and respective inputs using genomic DNA from different Drosophila species. RNA-seq was performed in a non-stranded manner without replicates for two Drosophila species.
2014-04-28 | E-GEOD-48251 | biostudies-arrayexpress
Project description:We generated F1 hybrids of each of the sister species A. halleri and A. lyrata with their outgroup relative of A. thaliana and monitored allele-specific levels of expression in standard growth conditions, in response to dehydration or cold exposure. This data allowed us to map the genome-wide distribution of cis-regulatory mutations active in three distinct environments reflecting divergent adaptations of the two species. Because the sister species were both crossed to an outgroup species, it was possible to assign a phylogenetic origin to cis-acting mutations. Cis-acting mutations observed in only one of the two hybrids were likely to be derived, whereas those observed in both hybrids either predate predated the split between the two species or arose along the A. thaliana lineage. By contrasting the distribution of cis-regulatory mutations derived in the A. halleri to those derived on the A. lyrata lineage, we could establish relative rates of cis-acting evolution across polygenic molecular functions and detect lineage-specific polygenic adaptation to environmental challenges. A.thalianaxA.lyrata under cold, dehydration and standard conditions, 3 biological replicates; A.thalianaxA.halleri under cold, dehydration and standard conditions, 3 biological replicates; toal 18 RNA-seq samples
2016-06-01 | E-GEOD-80462 | biostudies-arrayexpress
Project description:Transcriptional networks have been shown to evolve very rapidly, prompting questions as to how such changes arise and are tolerated. Recent comparisons of transcriptional networks across species have implicated variations in the cis-acting DNA sequences near genes as the main cause of divergence. What is less clear is how these changes interact with trans-acting changes occurring elsewhere in the genetic circuit. Here, we report the discovery of a system of compensatory trans and cis mutations in the yeast AP-1 transcriptional network that allows for conserved transcriptional regulation despite continued genetic change. We pinpoint a single species, the fungal pathogen Candida glabrata, in which a trans mutation has occurred very recently in a single AP-1 family member distinguishing it from its Saccharomyces ortholog. Comparison of chromatin immunoprecipitation profiles between Candida and Saccharomyces shows that, despite their different DNA binding domains, the AP-1 orthologs regulate a conserved block of genes. This conservation is enabled by concomitant changes in the cis-regulatory motifs upstream of each gene. Thus, both trans and cis mutations have perturbed the yeast AP-1 regulatory system in such a way as to compensate for one another. This demonstrates an example of “co-evolution” between a DNA-binding transcription factor and its cis-regulatory site, reminiscent of the co-evolution of protein binding partners. 3 Experiments were performed. Three replicates CgAp1-TAP was ChIPped under MMS treatment (GSM397447..GSM397449), two replicates each of ScYap1R79K and ScYap4K252R (GSM594724..GSM594727), were ChIPped under MMS treatment.
2010-09-17 | E-GEOD-15818 | biostudies-arrayexpress
Project description:Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects on gene expression are due to nearby genetic variants, trans effects are due to distal genetic variants that affect diffusible elements such as transcription factors. However, as previous studies have mostly assessed the impacts of cis and trans effects at the gene level, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we used massively parallel reporter assays to directly measure cis and trans effects between human and mouse embryonic stem cells at thousands of individual regulatory elements, including enhancers as well as promoters of both protein-coding and long non-coding RNA genes. Our approach revealed that cis effects are widespread across regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we found that trans effects are rare but stronger in enhancers than promoters, and can be attributed to a subset of transcription factors that are differentially expressed between human and mouse. While previous gene-based studies have found extensive co-occurrence of cis and trans effects in opposite directions that stabilize gene expression between species—or compensatory cis-trans effects—we find that cis-trans compensation is uncommon within individual regulatory elements. Moreover, regulatory elements that do show compensatory cis-trans effects are often less redundant than regulatory elements lacking compensatory cis-trans effects. Thus, our results are consistent with a model wherein compensatory cis-trans effects occur more often through crosstalk between multiple redundant regulatory elements than within a single individual regulatory element. Together, these results indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.
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Project description:Transcriptional networks have been shown to evolve very rapidly, prompting questions as to how such changes arise and are tolerated. Recent comparisons of transcriptional networks across species have implicated variations in the cis-acting DNA sequences near genes as the main cause of divergence. What is less clear is how these changes interact with trans-acting changes occurring elsewhere in the genetic circuit. Here, we report the discovery of a system of compensatory trans and cis mutations in the yeast AP-1 transcriptional network that allows for conserved transcriptional regulation despite continued genetic change. We pinpoint a single species, the fungal pathogen Candida glabrata, in which a trans mutation has occurred very recently in a single AP-1 family member distinguishing it from its Saccharomyces ortholog. Comparison of chromatin immunoprecipitation profiles between Candida and Saccharomyces shows that, despite their different DNA binding domains, the AP-1 orthologs regulate a conserved block of genes. This conservation is enabled by concomitant changes in the cis-regulatory motifs upstream of each gene. Thus, both trans and cis mutations have perturbed the yeast AP-1 regulatory system in such a way as to compensate for one another. This demonstrates an example of “co-evolution” between a DNA-binding transcription factor and its cis-regulatory site, reminiscent of the co-evolution of protein binding partners.
2010-09-17 | GSE15818 | GEO
Project description:Gene regulation occurs through trans-acting factors (e.g. transcription factors) acting on cis-regulatory elements (e.g. enhancers). Massively parallel reporter assays (MPRAs) functionally survey large numbers of cis-regulatory elements for regulatory potential, but do not identify the trans-acting factors that mediate any observed effects. Here we include preliminary data from a pilot transMPRA experiment — a reporter assay that efficiently combines multiplex CRISPR-mediated perturbation and MPRAs to identify trans-acting factors that modulate the regulatory activity of specific enhancers.
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Project description:We generated F1 hybrids of each of the sister species A. halleri and A. lyrata with their outgroup relative of A. thaliana and monitored allele-specific levels of expression in standard growth conditions, in response to dehydration or cold exposure. This data allowed us to map the genome-wide distribution of cis-regulatory mutations active in three distinct environments reflecting divergent adaptations of the two species. Because the sister species were both crossed to an outgroup species, it was possible to assign a phylogenetic origin to cis-acting mutations. Cis-acting mutations observed in only one of the two hybrids were likely to be derived, whereas those observed in both hybrids either predate predated the split between the two species or arose along the A. thaliana lineage. By contrasting the distribution of cis-regulatory mutations derived in the A. halleri to those derived on the A. lyrata lineage, we could establish relative rates of cis-acting evolution across polygenic molecular functions and detect lineage-specific polygenic adaptation to environmental challenges.
2016-06-01 | GSE80462 | GEO
Project description:Phenotypic differences between closely related species are thought to arise primarily from changes in gene expression due to mutations in cis-regulatory sequences (enhancers). However, it has remained unclear how frequently mutations alter enhancer activity or create functional enhancers de novo. Here we use STARR-seq, a recently developed quantitative enhancer assay, to determine genome-wide enhancer activity profiles for five Drosophila species in the constant trans-regulatory environment of Drosophila melanogaster S2 cells. We find that the functions of a large fraction of D. melanogaster enhancers are conserved for their orthologous sequences owing to selection and stabilizing turnover of transcription factor motifs. Moreover, hundreds of enhancers have been gained since the D. melanogaster-Drosophila yakuba split about 11 million years ago without apparent adaptive selection and can contribute to changes in gene expression in vivo. Our finding that enhancer activity is often deeply conserved and frequently gained provides functional insights into regulatory evolution.
2014-04-28 | GSE48251 | GEO
Project description:The spatiotemporal specific gene expression is regulated by cell type-specific regulatory elements including enhancers, silencers and insulators etc. The massively parallel reporter assay (MPRA) methods like STARR-seq facilitate the systematic study of DNA sequence intrinsic enhancer activities in a large scale. However, when applied to human cells, it remains challenging to identify and quantify cell type-specific active enhancers in the genome-wide scale with high-resolution, due to the large size of human genome. In this study, we selected the H3K4me1 associated dinucleosome with the linker DNA sequences as candidate enhancer sequences in two different human cell lines and performed ChIP-STARR-seq to quantify the cell type-specific enhancer activities with high-resolution in a genome-wide scale. Furthermore, we investigated how the activity landscape of enhancer repository would change when transferred from native cells (cis activity) to another cell lines (trans activity). Using ChIP-STARR-seq of the candidate enhancers in native cells and another type of cells, we obtained enhancers cis activity maps and trans activity maps in two different cell lines. The cis and trans activity maps enabled us to identify cell type-specific active enhancers, with enrichment of motifs of differentially expressed TFs. Comparisons between the cis and trans activity maps revealed general consistent regulatory property with different levels of activity in the two cell types, suggesting the sequence intrinsic regulatory properties keep similar in different type of cells. This study provides a new perspective of sequence intrinsic enhancer activities in different types of cells.
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Project description:Gene-expression divergence between species shapes morphological evolution, but the molecular basis is largely unknown. Here we show cis- and trans-regulatory elements and chromatin modifications on gene-expression diversity in genetically tractable Arabidopsis allotetraploids. In Arabidopsis thaliana and Arabidopsis arenosa, both cis and trans with predominant cis-regulatory effects mediate gene-expression divergence. The majority of genes with both cis- and trans-effects are subjected to compensating interactions and stabilizing selection. Interestingly, chromatin modifications correlate with cis - and trans -regulation. In F1 allotetraploids, Arabidopsis arenosa trans factors predominately affect allelic expression divergence. Arabidopsis arenosa trans factors tend to upregulate Arabidopsis thaliana alleles, whereas Arabidopsis thaliana trans factors up- or down-regulate Arabidopsis arenosa alleles. In resynthesized and natural allotetraploids, trans effects drive expression of both homoeologous loci into the same direction. We provide evidence for natural selection and chromatin regulation in shaping gene-expression diversity during plant evolution and speciation. Examination of gene expression in 5 tetraploid Arabidopsis using mRNA-seq
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