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Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [Capture Hi-C-seq]

ABSTRACT: Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [Capture Hi-C-seq]

PROVIDER: PRJNA515753 | ENA |

REPOSITORIES: ENA

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Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression

Project description:Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression

| PRJNA515752 | ENA

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [Capture Hi-C-seq]

Project description:The genome is organized in megabasesized three-dimensional units, called Topologically Associated Domains (TADs), that are separated by boundaries. TADs bring distant cis-regulatory elements into proximity, facilitated by the cooperative action of cohesin and the DNA binding factor CTCF. However, how TADs and their boundaries impinge on enhancer function remains an open question. Here, we investigate TAD function in vivo in mice at the Sox9/Kcnj locus. We find that TADs are formed by a redundant system of CTCF sites requiring the removal of all major sites within the TAD and at the boundary for two neighboring TADs to fuse. TAD fusion resulted in a low degree of regulatory spread from the Sox9 to the Kcnj TAD, but no major changes in gene expression, indicating that TAD structures provide robustness and precision, but are not essential for developmental gene regulation. Gene misexpression and consecutive disease phenotypes, however, were attained by re-directing regulatory activity through inversions and/or the re-positioning of boundaries. Thus, efficient re-wiring of enhancer promoter interaction and aberrant disease causing gene activation is not induced by a mere loss of insulation but requires the re-direction of contacts.

2019-06-01 | GSE125291 | GEO

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ChIP-Seq]

Project description:Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ChIP-Seq]

| PRJNA515754 | ENA

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ATAC-Seq]

Project description:Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ATAC-Seq]

| PRJNA515755 | ENA

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ATAC-Seq]

2019-06-01 | GSE125292 | GEO

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ChIP-Seq]

2019-06-01 | GSE125293 | GEO

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-06-01 | GSE125294 | GEO

CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression [Hi-C]

Project description:CTCF is an 11-zinc-finger DNA-binding protein that acts as a transcriptional repressor and insulator, as well as an architectural protein required for 3D genome folding. CTCF mediates long-range chromatin looping and is enriched at the boundaries of topologically associating domains (TADs), which are sub-megabase chromatin structures composed of genomic regions with high contact frequency. Although CTCF is essential for cycling cells and developing embryos, its in vitro removal has only modest effects over gene expression, challenging the generally accepted idea that TADs facilitate enhancer-promoter interactions within gene regulatory landscapes. However, the effects of an altered CTCF-mediated chromatin structure on gene regulation in vivo are poorly understood. Here, we have generated a ctcf knockout mutant in zebrafish that allows us to monitor the effect of CTCF loss of function during embryo patterning and organogenesis. CTCF absence leads to a loss of chromatin structure in zebrafish embryos and affects the expression of thousands of genes, among them many developmental genes. In addition, we show that chromatin accessibility, both at CTCF sites and at developmental cis-regulatory elements (CREs), is severely compromised in ctcf mutants. Probing chromatin interactions from developmental genes at high resolution, we further demonstrate that promoters fail to fully establish long-range contacts with their associated regulatory landscapes, leading to altered gene expression patterns during development. Therefore, our results demonstrate that CTCF and TADs are essential to finetune gene expression during embryonic development, providing the structural basis for the establishment of developmental gene regulatory landscapes.

2021-08-02 | GSE156097 | GEO

CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression [Hi-ChIP]

2021-08-02 | GSE175706 | GEO

Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs

Project description:HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs). We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet "DNA loops". Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in Vertebrates. The chromatin binding of the RNA polymerase II and the sub-unit Med12 of the Mediator complexe were analysed by ChIP-sequencing mouse distal E11.5 forelimb. This approach allowed us to identify the position of limb-specific enhancers.

2013-11-19 | E-GEOD-52483 | biostudies-arrayexpress

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