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Hormone-responsive enhancer-activity maps reveal predictive motifs, indirect repression, and targeting of closed chromatin

ABSTRACT: Steroid hormones act as important developmental switches and their nuclear receptors regulate many genes. However, few hormone-dependent enhancers have been characterized and important aspects of their sequence architecture, cell type-specific activating and repressing functions, or the regulatory roles of their chromatin structure have remained unclear. We used STARR-seq, a recently developed enhancer-screening assay, and ecdysone signaling in two different Drosophila cell types to derive the first genome-wide hormone-dependent enhancer activity maps. We demonstrate that enhancer activation depends on cis-regulatory motif combinations that differ between cell types and can predict cell type-specific ecdysone targeting. Activated enhancers are often not accessible prior to induction. Enhancer repression following hormone treatment is independent of receptor motifs and receptor binding to the enhancer as we show using ChIP-seq, but appears to rely on motifs for other factors, including Eip74. Our strategy is applicable to study signal-dependent enhancers for different pathways and across organisms.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE47691 | GEO | 2014/03/27

SECONDARY ACCESSION(S): PRJNA207301

REPOSITORIES: GEO

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Hormone-responsive enhancer-activity maps reveal predictive motifs, indirect repression, and targeting of closed chromatin

Project description:Steroid hormones act as important developmental switches and their nuclear receptors regulate many genes. However, few hormone-dependent enhancers have been characterized and important aspects of their sequence architecture, cell type-specific activating and repressing functions, or the regulatory roles of their chromatin structure have remained unclear. We used STARR-seq, a recently developed enhancer-screening assay, and ecdysone signaling in two different Drosophila cell types to derive the first genome-wide hormone-dependent enhancer activity maps. We demonstrate that enhancer activation depends on cis-regulatory motif combinations that differ between cell types and can predict cell type-specific ecdysone targeting. Activated enhancers are often not accessible prior to induction. Enhancer repression following hormone treatment is independent of receptor motifs and receptor binding to the enhancer as we show using ChIP-seq, but appears to rely on motifs for other factors, including Eip74. Our strategy is applicable to study signal-dependent enhancers for different pathways and across organisms. STARR-seq was performed in S2 and OSC cells treated with ecdysone in two replicates. DHS-seq before and after treatment was done with single-end sequencing in two replicates. RNA-seq (with and without ecdysone) was performed with a strand-specific protocol using single-end sequencing in two replicates in S2. ChIP-seq (with and without ecdysone) was performed single-end sequencing in two replicates in S2 cells.

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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.

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Genome-wide quantitative enhancer activity maps identified by STARR-seq

Project description:Genomic enhancers are important regulators of gene expression, but their identification is a challenge and methods depend on indirect measures of activity. We developed a method termed STARR-seq to directly and quantitatively assess enhancer activity for millions of candidates from arbitrary sources of DNA, enabling screens across entire genomes. When applied to the Drosophila genome, STARR-seq identifies thousands of cell type-specific enhancers across a broad continuum of strengths, linking differential gene expression to differences in enhancer activity and creating a genome-wide quantitative enhancer map. This map reveals the highly complex regulation of transcription, with several independent enhancers for both developmental regulators and ubiquitously expressed genes. STARR-seq can be used to identify and quantitate enhancer activity in other eukaryotes, including human. STARR-seq was performed in S2 and OSC cells with paired-end sequencing in two replicates and respective inputs. DHS-seq was done with single-end sequencing in two replicates for S2 and OSC cells. RNA-seq was performed with a strand-specific protocol using single-end sequencing in two replicates within S2 and OSC cells. STARR-seq was also performed in HeLa cells with single-end sequencing with a respective input.

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2014-04-02 | GSE49809 | GEO

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2013-03-15 | E-GEOD-33367 | biostudies-arrayexpress

Genome-wide quantitative enhancer activity maps identified by STARR-seq

2013-01-17 | GSE40739 | GEO

High-resolution dissection of human cell type-specific enhancers in cis and trans activities

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.

2023-09-22 | GSE243793 | GEO

Global Quantitative Mapping of Enhancer Activity in Rice Genome by STARR-seq

Project description:Enhancers are important regulators of gene expression, but their identification is a challenge in plants. STARR-seq is a method measuring directly the enhancer activity of millions fragments in parallel, which had been successfully used to identify enhancers in Drosophila and human genomes. Here we present a global map of rice enhancers whose activities are quantitatively determined by STARR-seq.We also predicted intergenic enhancers based on DNase I hypersensitivity as described in a previously published work. Predicted enhancers overlap poorly with STARR-seq enhancers, only about 400 sites accounting for 3-4% of total enhancers identified by these two different methods. In summary, our results of STARR-seq reveal that enhancers in a plant genome differ from animal enhancers in several aspects and provide a regulatory element resource for further functional and mechanistic studies in different contexts

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