Self-balanced regulation by the long non-coding RNA Lockd on the cell cycle progression of cortical neural progenitor cells through counteracting cis and trans roles
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PROVIDER: PRJNA698350 | ENA |
REPOSITORIES: ENA
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Project description:Neural stem/progenitor cells (NSPCs) undergo active proliferation and exit the cell cycle upon precise regulation to produce differentiated progenies in order. Long non-coding RNAs (lncRNAs) have emerged as critical players in the developmental processes of NSPCs; however, relatively few have been shown to regulate the cell cycle in vivo directly. Here, we identified an NSPC-expressed lncRNA Lockd (lncRNA downstream of Cdkn1b) in the developing forebrain. Using in vivo loss of function models by premature termination of Lockd transcription via knockin polyadenylation signals or shRNA-mediated knockdown of Lockd (Lockd-KD), we show that Lockd is required for proper cell cycle progression of cortical NSPCs and the production of TBR2+ intermediate neural progenitor cells during cortical development. Interestingly, a comparison of genetic profiling in the two models reveals that Lockd promotes the expression of two counteracting cell cycle-related genes, Cdkn1b in cis and Ccnd1 in trans. Overexpression of Ccnd1 or Cdkn1b-KD can rescue the cellular phenotypes of reduced cycling progenitors in Lockd-KD. Our results imply that lncRNA could act through distinct cis and trans mechanisms to achieve a self-balanced function.
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Project description:Gene expression is regulated both by cis elements, which are DNA segments closely linked to the genes they regulate, and by trans activating factors, which are usually proteins capable of diffusing to unlinked genes. Understanding the patterns and sources of regulatory variation is crucial for understanding phenotypic and genome evolution. Here, we investigate the global patterns of gene expression evolution in Saccharomyces cerivisiae. We report statistical methods useful in quantifying cis and trans regulation using next generation sequencing data. Using these methods, measured genome-wide allele-specific expression by deep sequencing to investigate the genetic architecture of gene regulatory variation between two strains of Saccharomyces cerevisiae. We find that expression polymorphism in yeast is common for both cis and trans regulation, though trans variation is more common. Our detailed analyses of the effects of functional constraint on expression variation as indicated by measures such as protein connectivity, gene essentiality, and the ratio of nonsynonymous substitutions to synonymous substitutions clearly reveal that both classes of variation are under purifying selection, but trans variation is more sensitive to selective constraint. Comparing interspecific expression divergence between S. cerevisiae and S. paradoxus to our intraspecific variation suggests that natural selection strongly influences the patterns of variation we observe. Further analyses revealed that cis divergence is more frequently mediated by positive Darwinian selection than trans divergence, which is compatible with neutral evolution. Study the gene expression patterns in two strains of yeast (BY and RM)
2010-04-02 | E-GEOD-20749 | biostudies-arrayexpress
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
2012-05-31 | E-GEOD-29687 | biostudies-arrayexpress
Project description:Gene expression evolution can be caused by changes in cis- or trans-regulatory elements or both. As cis and trans regulation operate through different molecular mechanisms, cis and trans mutations may show different inheritance patterns and may be subjected to different selective constraints. To investigate these issues, we obtained and analyzed gene expression data from two Saccharomyces cerevisiae strains and their hybrid, using high-throughput sequencing. Our data indicate that compared to other types of genes, those with antagonistic cis-trans interactions are more likely to exhibit over- or under-dominant inheritance of expression level. Moreover, in accordance with previous studies, genes with trans variants tend to have a dominant inheritance pattern while cis variants are enriched for additive inheritance. In addition, cis regulatory differences contribute more to expression differences between species than within species, whereas trans regulatory differences show a stronger association between divergence and polymorphism. Our data indicate that in the trans component of gene expression differences genes subjected to weaker selective constraints tend to have an excess of polymorphism over divergence compared to those subjected to stronger selective constraints. In contrast, in the cis component, this difference between genes under stronger and weaker selective constraint is mostly absent. To explain these observations, we propose that purifying selection more strongly shapes trans polymorphism than cis polymorphism. Study the gene expression patterns in two strains of yeast (BY and RM)
2013-11-10 | E-GEOD-46838 | biostudies-arrayexpress
Project description:Gene expression is regulated both by cis elements, which are DNA segments closely linked to the genes they regulate, and by trans activating factors, which are usually proteins capable of diffusing to unlinked genes. Understanding the patterns and sources of regulatory variation is crucial for understanding phenotypic and genome evolution. Here, we investigate the global patterns of gene expression evolution in Saccharomyces cerivisiae. We report statistical methods useful in quantifying cis and trans regulation using next generation sequencing data. Using these methods, measured genome-wide allele-specific expression by deep sequencing to investigate the genetic architecture of gene regulatory variation between two strains of Saccharomyces cerevisiae. We find that expression polymorphism in yeast is common for both cis and trans regulation, though trans variation is more common. Our detailed analyses of the effects of functional constraint on expression variation as indicated by measures such as protein connectivity, gene essentiality, and the ratio of nonsynonymous substitutions to synonymous substitutions clearly reveal that both classes of variation are under purifying selection, but trans variation is more sensitive to selective constraint. Comparing interspecific expression divergence between S. cerevisiae and S. paradoxus to our intraspecific variation suggests that natural selection strongly influences the patterns of variation we observe. Further analyses revealed that cis divergence is more frequently mediated by positive Darwinian selection than trans divergence, which is compatible with neutral evolution.
2010-04-02 | GSE20749 | GEO
Project description:Gene regulation can evolve either by cis-acting local changes to regulatory element DNA sequences or by global changes to the trans-acting regulatory environment; however, the modes favored during recent human evolution are unknown. To date, studies investigating gene regulatory divergence between closely-related species have produced limited estimates on the relative contributions of cis and trans effects on DNA regulatory element activities at a global-scale. By leveraging a comparative ATAC-STARR-seq framework, we identified 10,779 regulatory regions with divergent activity in cis and 10,608 regulatory regions with divergent activity in trans between human and rhesus macaque lymphoblastoid cell lines (LCLs). This revealed substantially more trans effects than predicted and indicates trans-regulatory mechanisms play a larger role in human evolution than previously expected. We also discover that most species-specific regulatory elements (67%) diverge in both cis and trans, suggesting these two mechanisms jointly drive divergent regulatory activity in a single sequence.
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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. 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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