Resolution of a human super-enhancer by targeted genome randomisation [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1211994 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32033553_1.fastq.gz | Fastqsanger.gz | |||
| SRR32033553_2.fastq.gz | Fastqsanger.gz | |||
| SRR32033554_1.fastq.gz | Fastqsanger.gz | |||
| SRR32033554_2.fastq.gz | Fastqsanger.gz | |||
| SRR32033555_1.fastq.gz | Fastqsanger.gz |
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Project description:Resolution of a human super-enhancer by targeted genome randomisation [ONT]
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Project description:Human gene expression is controlled from distance via enhancers, which can form longer ‘super-enhancer’-regions of intense regulatory activity. Whether super-enhancers constitute a separate regulatory paradigm remains unclear, largely due to the difficulty of dissecting the contributions and interactions of individual elements within their natural chromosomal context. To address this challenge, we developed enhancer scrambling, a high-throughput strategy to generate stochastic inversions and deletions of targeted enhancer regions by combining CRISPR prime editing insertion of symmetrical loxP sites with Cre recombinase-induced rearrangements. We applied our approach to dissect a distal super-enhancer of the OTX2 gene, generating up to 134 alternative regulatory configurations in a single experiment, and establishing how they drive gene expression and chromatin accessibility, as well as the individual contributions of its elements to this activity. Surprisingly, the presence of the sequence containing a single DNase I hypersensitive site predominantly controls OTX2 expression. Our findings highlight that enhancer-driven regulation of some highly expressed, cell-type-specific genes can rely on an individual element within a cluster of non-interacting, dispensable components, and suggest a simple functional core to a subset of super-enhancers. The targeted randomisation method to scramble enhancers can scale to resolve many super-enhancers and human gene regulatory landscapes.
2025-01-20 | GSE287267 | GEO
Project description:Resolution of a human super-enhancer by targeted genome randomisation [Amplicon-seq]
| PRJNA1211996 | ENA
Project description:Human gene expression is controlled from distance via enhancers, which can form longer ‘super-enhancer’-regions of intense regulatory activity. Whether super-enhancers constitute a separate regulatory paradigm remains unclear, largely due to the difficulty of dissecting the contributions and interactions of individual elements within their natural chromosomal context. To address this challenge, we developed enhancer scrambling, a high-throughput strategy to generate stochastic inversions and deletions of targeted enhancer regions by combining CRISPR prime editing insertion of symmetrical loxP sites with Cre recombinase-induced rearrangements. We applied our approach to dissect a distal super-enhancer of the OTX2 gene, generating up to 134 alternative regulatory configurations in a single experiment, and establishing how they drive gene expression and chromatin accessibility, as well as the individual contributions of its elements to this activity. Surprisingly, the presence of the sequence containing a single DNase I hypersensitive site predominantly controls OTX2 expression. Our findings highlight that enhancer-driven regulation of some highly expressed, cell-type-specific genes can rely on an individual element within a cluster of non-interacting, dispensable components, and suggest a simple functional core to a subset of super-enhancers. The targeted randomisation method to scramble enhancers can scale to resolve many super-enhancers and human gene regulatory landscapes.
2025-01-20 | GSE287266 | GEO
Project description:Human gene expression is controlled from distance via enhancers, which can form longer ‘super-enhancer’-regions of intense regulatory activity. Whether super-enhancers constitute a separate regulatory paradigm remains unclear, largely due to the difficulty of dissecting the contributions and interactions of individual elements within their natural chromosomal context. To address this challenge, we developed enhancer scrambling, a high-throughput strategy to generate stochastic inversions and deletions of targeted enhancer regions by combining CRISPR prime editing insertion of symmetrical loxP sites with Cre recombinase-induced rearrangements. We applied our approach to dissect a distal super-enhancer of the OTX2 gene, generating up to 134 alternative regulatory configurations in a single experiment, and establishing how they drive gene expression and chromatin accessibility, as well as the individual contributions of its elements to this activity. Surprisingly, the presence of the sequence containing a single DNase I hypersensitive site predominantly controls OTX2 expression. Our findings highlight that enhancer-driven regulation of some highly expressed, cell-type-specific genes can rely on an individual element within a cluster of non-interacting, dispensable components, and suggest a simple functional core to a subset of super-enhancers. The targeted randomisation method to scramble enhancers can scale to resolve many super-enhancers and human gene regulatory landscapes.
2025-01-20 | GSE287268 | GEO
Project description:Using GRO-Seq, we find extensive regulation of enhancer RNAs (eRNA) within super-enhancers in response to lipopolysaccharide treatment in macrophages. Both activation and repression of gene expression are associated with super-enhancers and eRNA transcription dynamics. Co-treatment of LPS and the anti-inflammatory drug dexamethasone targeted specific super-enhancers by attenuating their eRNA expression, leading to reduced expression of key inflammatory genes. We propose that super-enhancers function as molecular rheostats integrating the binding profiles of key regulators to produce dynamic profiles of gene expression. Nascent transcriptome (GRO-Seq) analysis over a time course (0, 20, 60, 180 min) of Lipopolisaccharide and Dexamethasone signaling in mouse bone marrow-derived macrophages.
2014-12-25 | E-GEOD-60857 | biostudies-arrayexpress
Project description:Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a novel TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.
2021-03-04 | PXD024505 |
Project description:Enhancer and super-enhancer landscape in ADPKD
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Project description:enhancer and super-enhancer landscape in ADPKD
| PRJNA781663 | ENA
Project description:Super-enhancers comprise of dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate their role in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-Seq for the master regulator STAT5, the glucocorticoid receptor, H3K27ac and MED1, identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5 binding sites within its three constituent enhancers. Individually, only the most distal site displayed significant enhancer activity. However, combinatorial mutations showed that the 1,000-fold gene induction relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer, suggesting an enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insight into the complexity of cell-specific and hormone-regulated genes. ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, RNA Pol II, and H3K4me3 in wild type (WT) mammary tissues at day one of lactation (L1), and ChIP-Seq for STAT5A, GR, H3K27ac, MED1, NFIB, ELF5, and H3K4me3 in WT mammary tissues at day 13 of pregnancy (p13). ChIP-Seq for STAT5A, GR, H3K27a in Wap-delE1a, -delE1b, -delE1c, -delE2 and -delE3 mutant mammary tissues at L1, and ChIP-Seq for NFIB and ELF5 in Wap-delE1b and -delE1c mutant mammary tissues at L1. ChIP-Seq for H3K4me3 in mammary-epthelial cells at p13 and L1. DNase-seq in WT mammary tissues at L1 and DNase-seq in Wap-delE1a, -delE1c, and -delE3 mutant mammary tissues at L1.
2016-05-31 | E-GEOD-74826 | biostudies-arrayexpress