Analysis of enhancer-promoter connectivity alterations
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001007411 | EGA |
REPOSITORIES: EGA
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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.
2023-12-31 | GSE213501 | GEO
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 as a cis-regulatory element (CRE), plays a critical role in gene regulation at many stages of cell growth. Meanwhile, enhancers in cancer cells also act as a regulator controlling oncogene transcription. In this study, we did a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin status, and expressions of two gastric cancer (GC) cell lines, compared with a human normal epithelial cell line. We found that GC-specific enhancers marked by histone modifications in gastric cancer can activate a population of genes including some oncogenes by enhancer-promoter (E-P) interactions. In addition, motif analysis of E-P interacted enhancers showed that three GC-specific TF sequences may regulate enhancer-interacting gene activation. We found MYB which is crucial for GC cellular growth and is activated by TCF7 regulated E-P loop. To validate this mechanism, we applied CRISPRi (dCas9-KRAB) induced transcriptional regulatory element inactivation in our target enhancer, the growth assay resulted in significant inhibition of cell growth in two GC cell lines. In conclusion, we found oncogene activation by aberrant loop formation that contributes to tumorigenesis in GC.
2024-04-22 | GSE247537 | GEO
Project description:Enhancer as a cis-regulatory element (CRE), plays a critical role in gene regulation at many stages of cell growth. Meanwhile, enhancers in cancer cells also act as a regulator controlling oncogene transcription. In this study, we did a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin status, and expressions of two gastric cancer (GC) cell lines, compared with a human normal epithelial cell line. We found that GC-specific enhancers marked by histone modifications in gastric cancer can activate a population of genes including some oncogenes by enhancer-promoter (E-P) interactions. In addition, motif analysis of E-P interacted enhancers showed that three GC-specific TF sequences may regulate enhancer-interacting gene activation. We found MYB which is crucial for GC cellular growth and is activated by TCF7 regulated E-P loop. To validate this mechanism, we applied CRISPRi (dCas9-KRAB) induced transcriptional regulatory element inactivation in our target enhancer, the growth assay resulted in significant inhibition of cell growth in two GC cell lines. In conclusion, we found oncogene activation by aberrant loop formation that contributes to tumorigenesis in GC.
2024-04-22 | GSE247536 | GEO
Project description:Enhancer as a cis-regulatory element (CRE), plays a critical role in gene regulation at many stages of cell growth. Meanwhile, enhancers in cancer cells also act as a regulator controlling oncogene transcription. In this study, we did a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin status, and expressions of two gastric cancer (GC) cell lines, compared with a human normal epithelial cell line. We found that GC-specific enhancers marked by histone modifications in gastric cancer can activate a population of genes including some oncogenes by enhancer-promoter (E-P) interactions. In addition, motif analysis of E-P interacted enhancers showed that three GC-specific TF sequences may regulate enhancer-interacting gene activation. We found MYB which is crucial for GC cellular growth and is activated by TCF7 regulated E-P loop. To validate this mechanism, we applied CRISPRi (dCas9-KRAB) induced transcriptional regulatory element inactivation in our target enhancer, the growth assay resulted in significant inhibition of cell growth in two GC cell lines. In conclusion, we found oncogene activation by aberrant loop formation that contributes to tumorigenesis in GC.
2024-04-22 | GSE262406 | GEO
Project description:Enhancers determine spatiotemporal gene expression programs by engaging with long-range promoters. However, it remains unknown how enhancers find their cognate promoters. We recently developed a RIC-seq technology to identify enhancer-promoter connectivity using pairwise interacting enhancer RNAs and promoter-derived noncoding RNAs in HeLa cells. Here, we apply this technology to generate high-confidence enhancer-promoter RNA interaction (EPRI) maps in six additional cell lines. Using these maps, we discover that 37.9% of the enhancer-promoter RNA interaction sites are overlapped with Alu sequences. These pairwise interacting Alu and non-Alu RNA sequences tend to be complementary and potentially form duplexes. Knockout of Alu elements compromises enhancer-promoter looping, whereas Alu insertion or CRISPR-dCasRx-mediated Alu tethering to unregulated promoter RNAs can create new loops to homologous enhancers. Importantly, mapping 535,404 noncoding risk variants back to the EPRI maps enabled us to construct variant-to-function maps for interpreting their molecular functions, including 15,318 deletions or insertions in 11,677 Alu elements that affect 6,497 protein-coding genes. We further demonstrate that polymorphic Alu insertion at PTK2 enhancer can promote tumorigenesis. Our study uncovers a principle for determining enhancer-promoter pairing specificity and provides a framework to link noncoding risk variants to their molecular functions.
2023-05-11 | GSE190214 | GEO
Project description:The resolution limit of chromatin conformation capture methodologies (3Cs) has restrained their application in detection of fine-level chromatin structure mediated by cis-regulatory elements (CREs). Here we report two 3C-derived methods, Tri-4C and Tri-HiC, utilizing mult-restriction enzyme digestions capable of achieveing ultrafine genome digestion for targeted and global chromatin interaction mapping, respectively, at a one hundred basepair resolution. Tri-4C identified loops associated with CREs including those involving regulatory elements devoid of typical epigenomic marks, quantifatively revealing alterations in interaction networks underlying dynamic gene control. Tri-HiC successfully uncovers fine-gage enhancer:promoter (E:P) loops at genome-wide level, identifying > 20-fold more CRE loops than in situ HiC. In addition to refined loop detection, Tri-HiC also reveals interaction stripes and contact domain insulation from promoters and enhancers, revealing their loop extrusion behaviors resembling the topologically-associated domain (TAD) boundaries. Tri-4C and Tri-HiC provide robust approaches to achieve the high resolution interactome maps required for characterizing fine-gage regulatory chromatin interactions in analysis of development, homeostasis and disease.
2021-11-02 | GSE161014 | GEO
Project description:Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input “easy Hi-C” protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.
2020-07-31 | GSE116825 | GEO
Project description:Enhancer as a cis-regulatory element (CRE), plays a critical role in gene regulation at many stages of cell growth. Meanwhile, enhancers in cancer cells also act as a regulator controlling oncogene transcription. In this study, we did a comprehensive analysis of long-range chromatin interactions, histone modifications, chromatin status, and expressions of two gastric cancer (GC) cell lines, compared with a human normal epithelial cell line. We found that GC-specific enhancers marked by histone modifications in gastric cancer can activate a population of genes including some oncogenes by enhancer-promoter (E-P) interactions. In addition, motif analysis of E-P interacted enhancers showed that three GC-specific TF sequences may regulate enhancer-interacting gene activation. We found MYB which is crucial for GC cellular growth and is activated by TCF7 regulated E-P loop. To validate this mechanism, we applied CRISPRi (dCas9-KRAB) induced transcriptional regulatory element inactivation in our target enhancer, the growth assay resulted in significant inhibition of cell growth in two GC cell lines. In conclusion, we found oncogene activation by aberrant loop formation that contributes to tumorigenesis in GC.
2024-04-22 | GSE247538 | GEO
Project description:Enhancer Cis Elements Instruct Promoter-Enhancer Interaction, Promoter-Enhancer Insulation and Compartmental Segregation
| PRJNA881254 | ENA