Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA639862 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions leads to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer-promoter interactions.
2020-07-30 | GSE155324 | GEO
Project description:Aberrant activation of the TAL1 oncogene is associated with up to 60% of T-ALL patients and is involved in CTCF mediated genome organization within the TAL1 locus, suggesting the importance of the CTCF boundary in the molecular pathogenesis of T-ALL. Here, we show that deletion of CTCF binding site (CBS) or alternation of CTCF boundary orientation alters expression of the TAL1 oncogene in a cell context dependent manner. Deletion of the CTCF binding site located at -31 Kb upstream of TAL1 (-31CBS) reduces chromatin accessibility in the +51 enhancer and the TAL1 promoter I, and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter 1b that inhibits expression of TAL1 in erythroid cells, but not in T-ALL cells. However, in the TAL1 expressed T-ALL primary patient samples or cell line, the T-ALL prone TAL1 promoter IV specifically interacts with the +19 stem cell enhancer that is located 19 kb downstream of the TAL1 promoter and required for TAL1 transcription in the hematopoietic stem cell (HSC) stage. Inversion of -31CBS orientation, but not deletion of -31CBS, alters chromatin accessibility, enhancer/promoter histone modifications, CTCF-mediated topological associated domain (TAD), and enhancer/promoter interaction in the TAL1 locus leading to inhibition of TAL1 oncogene expression and TAL1-driven T cell leukemogenesis. Thus, our data reveal that the TAL1 +19 stem cell enhancer acts not only as stem cell enhancer, but also as a leukemia specific enhancer to activate the TAL1 oncogene in T-ALL. Manipulation of CTCF defined chromatin boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.
2020-04-06 | GSE135320 | GEO
Project description:Expression of Shh in the limb is dependent on a distant enhancer located 850kb away from the gene promoter. We performed chromatin conformation capture (4C-Seq) analysis of the Shh locus in E11.5 mouse limbs so as to better understand the relationship between this regulatory interaction and the structural organisation of the locus. The experiments were performed on wild-type animals as well as on animals carrying an engineered chromosomal inversion (INV(6-C2) (INV6)) . The different viewpoints used (Shh, ZRS, Nom1, Rbm33, Rnf32) enable to characterize the 3D organisation of the locus in the different contexts. The inversion INV6 disrupts the normal topological organisation of the Shh locus in a compact 3D-domain and prevents the physical and regulatory interaction between Shh and its limb enhancer, even though the genomic distance separating the two elements is reduced compared to WT.
2017-01-12 | E-MTAB-4980 | biostudies-arrayexpress
Project description:Higher order chromatin structure establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of individual loci within a topological domain (TAD) are not fully understood. The cystic fibrosis transmembrane conductance regulator (CFTR) gene provides a paradigm for investigating these mechanisms. CFTR occupies a TAD bordered by CTCF/cohesin binding sites within which are cell-type-selective cis-regulatory elements for the locus. We showed previously that intronic and extragenic enhancers, when occupied by specific transcription factors, are recruited to the CFTR promoter by a looping mechanism to drive gene expression. Here we use a combination of CRISPR/Cas9 editing of cis-regulatory elements and siRNA-mediated depletion of architectural proteins to determine the relative contribution of structural elements and enhancers to the higher order structure and expression of the CFTR locus. We found the boundaries of the CFTR TAD are conserved among diverse cell types and are dependent on CTCF and cohesin complex. Removal of an upstream CTCF-binding insulator alters the interaction profile, but has little effect on CFTR expression. Within the TAD, intronic enhancers recruit cell-type selective transcription factors and deletion of a pivotal enhancer element dramatically decreases CFTR expression, but has minor effect on its 3D structure. Examination of open chromatin region in Caco2 (colorectal adenocarcinoma cells), HBE (primary human bronchial epithelial cells), and primary adult human epididymis cells
2016-01-07 | E-GEOD-74709 | biostudies-arrayexpress
Project description:Enhancers play key roles in gene regulation. However, comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Through gene regulatory network modeling, we identified that dynamic cell state transitions, a critical missing component in prevalent enhancer discovery strategies, can be utilized to improve the cells’ sensitivity to enhancer perturbation. Guided by the modeling results, we performed a mid-transition CRISPRi-based enhancer screen utilizing human embryonic stem cell definitive endoderm differentiation as a dynamic transition system. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core lineage-specifying transcription factors (TFs), including many enhancers with weak to moderate effects. Integrating the screening results with enhancer activity measurements (ATAC-seq, H3K27ac ChIP-seq) and three-dimensional enhancer-promoter interaction information (CTCF looping, Hi-C), we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Together, our dynamic network-guided enhancer screen and the CIA enhancer prediction model provide generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.
2023-06-17 | PXD043070 | Pride
Project description:ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry
| PRJNA1045673 | ENA
Project description:ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry
| PRJNA991933 | ENA
Project description:Recent studies indicate that even a homogeneous population of cells display heterogeneity in gene expression and response to environmental stimuli. Although promoter structure critically influences the cell-to-cell variation of gene expression in bacteria and lower eukaryotes, it remains unclear what controls the gene expression noise in mammals. Here we report that CTCF decreases cell-to-cell variation of expression by stabilizing enhancer-promoter interaction. We show that CTCF binding sites are interwoven with enhancers within topologically-associated domains (TADs) and a positive correlation is found between CTCF binding and the activity of the associated enhancers. Deletion of CTCF sites using CRISPR/Cas9 compromises enhancer-promoter interactions. Using single-cell flow cytometry and single-molecule RNA-FISH assays, we demonstrate that knocking down of CTCF or deletion of a CTCF binding site results in increased cell-to-cell variation of gene expression, indicating that long-range promoter-enhancer interaction mediated by CTCF plays an important role in controlling the cell-to-cell variation of gene expression in mammalian cells.
2017-10-01 | GSE66343 | GEO
Project description:ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry [4C]
| PRJNA991935 | ENA
Project description:ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry [HiChIP]
| PRJNA991936 | ENA