scholarly journals Phylogenetic modeling of regulatory element turnover based on epigenomic data

2019 ◽  
Author(s):  
Noah Dukler ◽  
Yi-Fei Huang ◽  
Adam Siepel
Keyword(s):  
Dna Sequence ◽  
Target Genes ◽  
Evolutionary Dynamics ◽  
Regulatory Element ◽  
Probabilistic Modeling ◽  
Regulatory Elements ◽  
Turnover Rates ◽  
Modeling Framework ◽  
Model Free ◽  
Evolutionary Changes

AbstractEvolutionary changes in gene expression are often driven by gains and losses of cis-regulatory elements (CREs). The dynamics of CRE evolution can be examined using multi-species epigenomic data, but so far such analyses have generally been descriptive and model-free. Here, we introduce a probabilistic modeling framework for the evolution of CREs that operates directly on raw chromatin immunoprecipitation and sequencing (ChIP-seq) data and fully considers the phylogenetic relationships among species. Our framework includes a phylogenetic hidden Markov model, called epiPhyloHMM, for identifying the locations of multiply aligned CREs, and a combined phylogenetic and generalized linear model, called phyloGLM, for accounting for the influence of a rich set of genomic features in describing their evolutionary dynamics. We apply these methods to previously published ChIP-seq data for the H3K4me3 and H3K27ac histone modifications in liver tissue from nine mammals. We find that enhancers are gained and lost during mammalian evolution at about twice the rate of promoters, and that turnover rates are negatively correlated with DNA sequence conservation, expression level, and tissue breadth, and positively correlated with distance from the transcription start site, consistent with previous findings. In addition, we find that the predicted dosage sensitivity of target genes positively correlates with DNA sequence constraint in CREs but not with turnover rates, perhaps owing to differences in the effect sizes of the relevant mutations. Altogether, our probabilistic modeling framework enables a variety of powerful new analyses.

scholarly journals Phylogenetic Modeling of Regulatory Element Turnover Based on Epigenomic Data

2020 ◽  
Vol 37 (7) ◽  
pp. 2137-2152
Author(s):  
Noah Dukler ◽  
Yi-Fei Huang ◽  
Adam Siepel
Keyword(s):  
Dna Sequence ◽  
Target Genes ◽  
Evolutionary Dynamics ◽  
Regulatory Element ◽  
Probabilistic Modeling ◽  
Regulatory Elements ◽  
Turnover Rates ◽  
Modeling Framework ◽  
Model Free ◽  
Evolutionary Changes

Abstract Evolutionary changes in gene expression are often driven by gains and losses of cis-regulatory elements (CREs). The dynamics of CRE evolution can be examined using multispecies epigenomic data, but so far such analyses have generally been descriptive and model-free. Here, we introduce a probabilistic modeling framework for the evolution of CREs that operates directly on raw chromatin immunoprecipitation and sequencing (ChIP-seq) data and fully considers the phylogenetic relationships among species. Our framework includes a phylogenetic hidden Markov model, called epiPhyloHMM, for identifying the locations of multiply aligned CREs, and a combined phylogenetic and generalized linear model, called phyloGLM, for accounting for the influence of a rich set of genomic features in describing their evolutionary dynamics. We apply these methods to previously published ChIP-seq data for the H3K4me3 and H3K27ac histone modifications in liver tissue from nine mammals. We find that enhancers are gained and lost during mammalian evolution at about twice the rate of promoters, and that turnover rates are negatively correlated with DNA sequence conservation, expression level, and tissue breadth, and positively correlated with distance from the transcription start site, consistent with previous findings. In addition, we find that the predicted dosage sensitivity of target genes positively correlates with DNA sequence constraint in CREs but not with turnover rates, perhaps owing to differences in the effect sizes of the relevant mutations. Altogether, our probabilistic modeling framework enables a variety of powerful new analyses.

scholarly journals The pancreatic islet factor STF-1 binds cooperatively with Pbx to a regulatory element in the somatostatin promoter: importance of the FPWMK motif and of the homeodomain.

1995 ◽  
Vol 15 (12) ◽  
pp. 7091-7097 ◽  
Author(s):  
B Peers ◽  
S Sharma ◽  
T Johnson ◽  
M Kamps ◽  
M Montminy
Keyword(s):  
Target Genes ◽  
Gene Selection ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Cooperative Binding ◽  
Homeodomain Protein ◽  
Homeodomain Proteins ◽  
Target Sites

A number of homeodomain proteins have been shown to regulate cellular development by stimulating the transcription of specific target genes. In contrast to their distinct activities in vivo, however, most homeodomain proteins bind indiscriminately to potential target sites in vitro, suggesting the involvement of cofactors which specify target site selection. One such cofactor, termed extradenticle, has been shown to influence segmental morphogenesis in Drosophila melanogaster by binding cooperatively with certain homeodomain proteins to target regulatory elements. Here we demonstrate that STF-1, an orphan homeodomain protein required for pancreatic development in mammals, binds cooperatively to DNA with Pbx, the mammalian homolog of extradenticle. Cooperative binding with Pbx requires a pentapeptide motif (FPWMK) which is well conserved among a large subset of homeodomain proteins. The FPMWK motif is not sufficient to confer Pbx cooperativity on other homeodomain proteins, however; the N-terminal arm of the STF-1 homeodomain is also essential. As cooperative binding with Pbx occurs on only a subset of potential STF-1 target sites, our results suggest that Pbx may specify target gene selection in the developing pancreas by forming heterodimeric complexes with STF-1.

scholarly journals Genome-Wide cis-Regulatory Element Based Discovery of Auxin-Responsive Genes in Higher Plant

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 24
Author(s):  
Jianfei Wu ◽  
Fan Gao ◽  
Tongtong Li ◽  
Haixia Guo ◽  
Li Zhang ◽  
...  
Keyword(s):  
Target Genes ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Auxin Response ◽  
Higher Plant ◽  
Response Factors ◽  
Auxin Response Factors ◽  
Genome Wide ◽  
A Genome ◽  
Almost All

Auxin has a profound impact on plant physiology and participates in almost all aspects of plant development processes. Auxin exerts profound pleiotropic effects on plant growth and differentiation by regulating the auxin response genes’ expressions. The classical auxin reaction is usually mediated by auxin response factors (ARFs), which bind to the auxin response element (AuxRE) in the promoter region of the target gene. Experiments have generated only a limited number of plant genes with well-characterized functions. It is still unknown how many genes respond to exogenous auxin treatment. An economical and effective method was proposed for the genome-wide discovery of genes responsive to auxin in a model plant, Arabidopsis thaliana (A. thaliana). Our method relies on cis-regulatory-element-based targeted gene finding across different promoters in a genome. We first exploit and analyze auxin-specific cis-regulatory elements for the transcription of the target genes, and then identify putative auxin responsive genes whose promoters contain the elements in the collection of over 25,800 promoters in the A. thaliana genome. Evaluating our result by comparing with a published database and the literature, we found that this method has an accuracy rate of 65.2% (309/474) for predicting candidate genes responsive to auxin. Chromosome distribution and annotation of the putative auxin-responsive genes predicted here were also mined. The results can markedly decrease the number of identified but merely potential auxin target genes and also provide useful clues for improving the annotation of gene that lack functional information.

scholarly journals Recapitulating Evolutionary Divergence in a Single Cis-Regulatory Element Is Sufficient to Cause Expression Changes of the Lens Gene Tdrd7

2020 ◽  
Author(s):  
Juliana G Roscito ◽  
Kaushikaram Subramanian ◽  
Ronald Naumann ◽  
Mihail Sarov ◽  
Anna Shevchenko ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Mrna Level ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Phenotypic Differences ◽  
Evolutionary Changes ◽  
Mole Rat ◽  
Regulatory Mutations ◽  
Subterranean Mammals ◽  
And Function

Abstract Mutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR; Nannospalax galili) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved noncoding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated evolutionary changes in this element by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR–Cas9. Strikingly, this repressor replacement caused a more than 2-fold upregulation of Tdrd7 in the developing lens; however, increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, possibly explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.

scholarly journals Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

2021 ◽  
pp. gr.275901.121
Author(s):  
Alexandre Laverre ◽  
Eric Tannier ◽  
Anamaria Necsulea
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Large Scale ◽  
Target Genes ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Landscapes

Gene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve not only regulatory element sequences but also their chromatin contacts with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory landscapes constrains large-scale genome evolution. We show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is significantly associated with gene expression evolution.

scholarly journals Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

2021 ◽  
Author(s):  
Alexandre Laverré ◽  
Eric Tannier ◽  
Anamaria Necsulea
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Large Scale ◽  
Target Genes ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Landscapes

AbstractGene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve regulatory element sequences and their interactions with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory interactions constrains large-scale genome evolution. Notably, we show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is tightly linked to gene expression evolution.

scholarly journals Recapitulating evolutionary divergence in a single cis-regulatory element is sufficient to cause expression changes of the lens gene Tdrd7

2020 ◽  
Author(s):  
Juliana G. Roscito ◽  
Kaushikaram Subramanian ◽  
Ronald Naumann ◽  
Mihail Sarov ◽  
Anna Shevchenko ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Mrna Level ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Phenotypic Differences ◽  
Evolutionary Changes ◽  
Mole Rat ◽  
Regulatory Mutations ◽  
Subterranean Mammals ◽  
And Function

ABSTRACTMutations in cis-regulatory elements play important roles for phenotypic changes during evolution. Eye degeneration in the blind mole rat (BMR) and other subterranean mammals is significantly associated with widespread divergence of eye regulatory elements, but the effect of these regulatory mutations on eye development and function has not been explored. Here, we investigate the effect of mutations observed in the BMR sequence of a conserved non-coding element upstream of Tdrd7, a pleiotropic gene required for lens development and spermatogenesis. We first show that this conserved element is a transcriptional repressor in lens cells and that the BMR sequence partially lost repressor activity. Next, we recapitulated the evolutionary changes by precisely replacing the endogenous regulatory element in a mouse line by the orthologous BMR sequence with CRISPR-Cas9. Strikingly, this repressor element has a large effect, causing a more than two-fold up-regulation of Tdrd7 in developing lens. Interestingly, the increased mRNA level does not result in a corresponding increase in TDRD7 protein nor an obvious lens phenotype, likely explained by buffering at the posttranscriptional level. Our results are consistent with eye degeneration in subterranean mammals having a polygenic basis where many small-effect mutations in different eye-regulatory elements collectively contribute to phenotypic differences.

scholarly journals The Gene for the Embryonic Stem Cell Coactivator UTF1 Carries a Regulatory Element Which Selectively Interacts with a Complex Composed of Oct-3/4 and Sox-2

1999 ◽  
Vol 19 (8) ◽  
pp. 5453-5465 ◽  
Author(s):  
Masazumi Nishimoto ◽  
Akiko Fukushima ◽  
Akihiko Okuda ◽  
Masami Muramatsu
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Es Cells ◽  
Regulatory Element ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
General Mechanism ◽  
Octamer Motif ◽  
Biochemical Analyses ◽  
Binding Sequence

ABSTRACT UTF1 is a transcriptional coactivator which has recently been isolated and found to be expressed mainly in pluripotent embryonic stem (ES) cells (A. Okuda, A. Fukushima, M. Nishimoto, et al., EMBO J. 17:2019–2032, 1998). To gain insight into the regulatory network of gene expression in ES cells, we have characterized the regulatory elements governing UTF1 gene expression. The results indicate that the UTF1 gene is one of the target genes of an embryonic octamer binding transcription factor, Oct-3/4. UTF1 expression is, like the FGF-4 gene, regulated by the synergistic action of Oct-3/4 and another embryonic factor, Sox-2, implying that the requirement for Sox-2 by Oct-3/4 is not limited to the FGF-4 enhancer but is rather a general mechanism of activation for Oct-3/4. Our biochemical analyses, however, also reveal one distinct difference between these two regulatory elements: unlike the FGF-4 enhancer, the UTF1 regulatory element can, by its one-base difference from the canonical octamer-binding sequence, selectively recruit the complex comprising Oct-3/4 and Sox-2 and preclude the binding of the transcriptionally inactive complex containing Oct-1 or Oct-6. Furthermore, our analyses reveal that these properties are dictated by the unique ability of the Oct-3/4 POU-homeodomain that recognizes a variant of the Octamer motif in the UTF1 regulatory element.

scholarly journals Genome-wide annotation of gene regulatory elements linked to cell fitness

2021 ◽  
Author(s):  
Tyler S. Klann ◽  
Alejandro Barrera ◽  
Adarsh R. Ettyreddy ◽  
Ryan A. Rickels ◽  
Julien Bryois ◽  
...  
Keyword(s):  
Target Genes ◽  
Disease Risk ◽  
Regulatory Element ◽  
Cancer Cell Line ◽  
K562 Cells ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Cell Type Specificity ◽  
Cellular Processes ◽  
Genome Wide

AbstractNoncoding regulatory elements control gene expression and govern all biological processes. Epigenomic profiling assays have identified millions of putative regulatory elements, but systematically determining the function of each of those regulatory elements remains a substantial challenge. Here we adapt CRISPR-dCas9-based epigenomic regulatory element screening (CERES) technology to screen all >100,000 putative non-coding regulatory elements defined by open chromatin sites in human K562 leukemia cells for their role in regulating essential cellular processes. In an initial screen containing more than 1 million gRNAs, we discovered approximately 12,000 regulatory elements with evidence of impact on cell fitness. We validated many of the screen hits in K562 cells, evaluated cell-type specificity in a second cancer cell line, and identified target genes of regulatory elements using CERES perturbations combined with single cell RNA-seq. This comprehensive and quantitative genome-wide map of essential regulatory elements represents a framework for extensive characterization of noncoding regulatory elements that drive complex cell phenotypes and for prioritizing non-coding genetic variants that likely contribute to common traits and disease risk.

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