Inversion of a topological domain leads to restricted changes in its gene expression and affects inter-domain communication
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ABSTRACT:
PROVIDER: PRJNA748894 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15214334.fastq.gz | Fastqsanger.gz | |||
| SRR15214335.fastq.gz | Fastqsanger.gz | |||
| SRR18746545.fastq.gz | Fastqsanger.gz | |||
| SRR18746546.fastq.gz | Fastqsanger.gz | |||
| SRR18746547.fastq.gz | Fastqsanger.gz |
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Project description:The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors underlying genome topology, such as CTCF and cohesin, leads to modest alterations in gene expression, while genomic rearrangements involving boundaries of topologically associating domains (TADs) disrupt normal gene expression and can lead to pathological phenotypes. Here we inverted an almost entire TAD (245kb out of 300kb) within the X-inactivation centre (Xic), leaving its boundaries intact, which led to a significant rearrangement of topological contacts within the TAD, mostly in accordance to the orientation of underlying CTCF binding sites, and to an increase in contact insulation with the neighbouring TAD. Expression of most genes within the TAD remained unaffected in mutant mouse embryonic stem cells and during differentiation. Interestingly, expression in the neighbouring TAD of the noncoding transcript Xist, which controls X-chromosome inactivation, was ectopically upregulated. The same inversion in mouse embryos led to slight biases in Xist expression but normal patterns of X-chromosome inactivation. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighbouring TADs, highlighting the existence of mechanisms for inter-TAD communication.
2022-04-18 | GSE180617 | GEO
Project description:The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors (e.g. CTCF) underlying topologically associating domains (TADs) leads to modest alterations in gene expression, whereas genomic rearrangements involving TAD boundaries disrupt normal gene expression and can lead to pathological phenotypes. Here, we targeted the TAD neighboring that of the noncoding transcript Xist, which controls X-chromosome inactivation. Inverting 245 kb within the TAD led to expected rearrangement of CTCF-based contacts but revealed heterogeneity in the 'contact' potential of different CTCF sites. Expression of most genes therein remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression of Xist was ectopically upregulated. The same inversion in mouse embryos led to biased Xist expression. Smaller inversions and deletions of CTCF clusters led to similar results: rearrangement of contacts and limited changes in local gene expression, but significant changes in Xist expression in embryos. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighboring TADs, highlighting the existence of mechanisms of inter-TAD communication.
| S-EPMC9148567 | biostudies-literature
Project description:Divergent transcription from within bacterial intergenic regions frequently involves promoters dependent on alternative σ-factors. This is the case for the non-overlapping σ70- and σ54-dependent promoters that control production of the substrate-responsive regulator and enzymes for (methyl)phenol catabolism. Here, using an array of in vivo and in vitro assays, we identify transcription-driven supercoiling arising from the σ54-promoter as the mechanism underlying inter-promoter communication that results in stimulation of the activity of the σ70-promoter. The non-overlapping 'back-to-back' configuration of a powerful σ54-promoter and weak σ70-promoter within this system offers a previously unknown means of inter-sigmulon communication that renders the σ70-promoter subservient to signals that elicit σ54-dependent transcription without it possessing a cognate binding site for the σ54-RNA polymerase holoenzyme. This mode of control has the potential to be a prevalent, but hitherto unappreciated, mechanism by which bacteria adjust promoter activity to gain appropriate transcriptional control.
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Project description:Inversion evolutionary rates might limit the experimental identification of inversion breakpoints in non-model species
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Project description:Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct a 140 kb int1h inversion frequently found in patients diagnosed with Hemophilia A. With the use of directed molecular evolution, we developed a linked heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from int1h patient derived iPSCs, resulted in prominent correction of the inversion and restored Factor VIII mRNA expression. Our data suggest that the development of designer-recombinases represent an efficient and specific mean towards treatment of large gene inversions causing monogenic diseases.
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Project description:CTCF/cohesin play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and β-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters, and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. The findings reveal how 3D chromosome architecture can be encoded by genome sequence.
2015-08-13 | GSE71275 | GEO
Project description:Dominance reversal of inversion karyotypes - RNAseq
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Project description:Dominance reversal of inversion karyotypes - ATAC-seq
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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:Enhancers are tissue-specific regulatory DNA elements that can activate transcription of genes over distance. Their target genes most often locate in the same topologically associating domain (TAD). TADs are structural entities within chromosomes in which cohesin DNA loop extrusion supports intra-domain DNA contacts and CTCF-bound boundaries serve to halt and concentrate paralogous genes. Enhancers shared by multiple unrelated genes may be more common than those acting on paralogous gene clusters, but are underexplored. Here, we analyzed the interplay between an enhancer and two distal, functionally unrelated, genes residing at opposite domain boundaries. The enhancer stimulated boundary and gene-gene contacts and required cohesin as well as two intact domain boundaries to support gene activation. The two genes preferentially transcribed when spatially together, but did not rely on each other’s transcription, nor showed gene competition. Placing them and the enhancer in smaller domains caused their upregulation. Domain boundaries, therefore, can support long-range enhancer-promoter communication inside domains. Boundary proximity thereby matters as the distal enhancer functions more effectively inside smaller domains. We propose that smaller domains have more concentrated cohesin loop extrusion activity to facilitate enhancer action over distance.
2025-02-19 | GSE274831 | GEO