Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA562691 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10030400.fastq.gz | Fastqsanger.gz | |||
| SRR10030401.fastq.gz | Fastqsanger.gz | |||
| SRR10030402.fastq.gz | Fastqsanger.gz | |||
| SRR10030403.fastq.gz | Fastqsanger.gz | |||
| SRR10030404.fastq.gz | Fastqsanger.gz |
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Project description:Enhancer Cis Elements Instruct Promoter-Enhancer Interaction, Promoter-Enhancer Insulation and Compartmental Segregation
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Project description:Enhancers harbor instructions encoded for the interactions between cis-elements and transcription factors to orchestrate lineage specific gene programs. Here we developed a modified method for chromosome conformation capture (3C), named MID Hi-C, to reveal how in mouse embryonic stem cells differential cooperation of enhancers and the chromatin remodeler BAF, as instructed by the underlying transcription factor motifs, modulate enhancer-promoter communication. We show that BAF-dependent enhancers permit genomic interactions beyond enhancer boundaries. BAF-dependent enhancers do not dictate genomic interactions within enhancer-promoter loop domains but rather act to instruct remote enhancer-promoter communication. In contrast, BAF-independent enhancers interact with promoter regions within tightly insulated enhancer-promoter loop domains that are marked by promoter and enhancer boundary elements. In addition, enhancer activeness modulated by BAF enforces compartment segregation. Based on these observations, we propose that enhancer cis elements instruct with great precision BAF-induced enhancer-promoter communication and compartmental segregation.
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Project description:Background Genomic variations contribute to the phenotypic diversity of individuals. A number of polymorphisms in protein-coding regions that alter drug efficacy or lead to adverse reactions have been characterized; however, noncoding regions that affect drug responses are largely overlooked, except for a limited number of well-studied enhancers. Results We conducted a quantitative assessment of cis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) were further narrowed down by integrating data of PXR-binding sites in human primary hepatocytes and genome-wide association studies. We found more than 100-fold enrichments of the candidates to genetically associated loci with circulating levels of bilirubin and vitamin D, which implicated a link to adverse reactions of PXR ligands. We uncovered novel enhancers of UGT1A1 and TSKU through CRISPR/Cas9 knockout experiments. We identified alleles altering regulatory activities of UGT1A1 and CYP24A1enhancers by using luciferase reporter assay. Furthermore, our siRNA experiments revealed an unexpected impact of TSKU on the expression of vitamin D-metabolizing enzymes. Conclusions Our transcriptome-based assessment of CREs expanded the list of drug-inducible and PXR-mediated enhancers and super-enhancers. We identified regulatory alleles that alter drug-induced gene expressions, and discovered a novel molecular cascade associated with an adverse reaction. Our results contribute a precise understanding of the noncoding elements of the human genome underlying drug responses.
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Project description:Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the Samd14 locus (S14E) is required for survival in severe anemia. The S14E contains DNA binding motifs for GATA and TAL1, two transcription factors which bind to the enhancer and activate transcription during stress erythropoiesis. However, Samd14 is only one of dozens of anemia-activated genes. In a mouse model of acute anemia, we used single cell RNA sequencing to identify erythroid cell types which expanded and increased expression of genes that contain S14E-like cis-elements. Through orthogonal loss-of-function approaches (shRNA, sgRNA-guided Cas9 and Cas9-KRAB), we reveal that several S14E-like cis-elements are important for the expression of newly identified anemia induced genes, including the poorly studied Ssx-2 interacting protein (Ssx2ip). Ssx2ip expression was determined to play an important role in erythroid progenitor activity, cell cycle progression, and proliferation in anemia. Our results define a genome-wide mechanism in which S14E-like enhancers control transcriptional responses during erythroid regeneration. Furthermore, time course analysis of erythroid precursor gene activation in anemia revealed distinct transcriptional programs are established at earlier time points, distinct from S14E-like elements. These findings provide a framework to understand anemia-specific transcriptional mechanisms, ineffective erythropoiesis, anemia recovery and phenotypic variability within human populations.
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