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Omics score: 1000

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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			Action	DRS
	SRR8453400_1.fastq.gz	Fastqsanger.gz
	SRR8453400_2.fastq.gz	Fastqsanger.gz
	SRR8453401_1.fastq.gz	Fastqsanger.gz
	SRR8453401_2.fastq.gz	Fastqsanger.gz
	SRR8453402_1.fastq.gz	Fastqsanger.gz

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Publications

Functional dissection of the Sox9-Kcnj2 locus identifies nonessential and instructive roles of TAD architecture.

Despang Alexandra A Schöpflin Robert R Franke Martin M Ali Salaheddine S Jerković Ivana I Paliou Christina C Chan Wing-Lee WL Timmermann Bernd B Wittler Lars L Vingron Martin M Mundlos Stefan S Ibrahim Daniel M DM

Nature genetics 20190729 8

The genome is organized in three-dimensional units called topologically associating domains (TADs), through a process dependent on the cooperative action of cohesin and the DNA-binding factor CTCF. Genomic rearrangements of TADs have been shown to cause gene misexpression and disease, but genome-wide depletion of CTCF has no drastic effects on transcription. Here, we investigate TAD function in vivo in mouse limb buds at the Sox9-Kcnj2 locus. We show that the removal of all major CTCF sites at t ...[more]

PMID: 31358994

Similar Datasets

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. Overall design: We used Capture Hi-C enriching a 6 Mb region at the Sox9locus in Mus musculus to study the effects of CRISPR/Cas9-induced CTCF-site deletions, insertions, and inversions on the genomic landscape. We analysed wildtype and homozygous mutant limb buds (from 9 mutants) as singleton (limb buds of 3-8 embryos for each condition), as it was done in similar studies (See Franke et la., Nature, 2016 or Bianco et al., Nat. Gen. 2018). Embryonic E12.5 limb tissue was used.

2019-06-01 | GSE125291 | GEO

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 [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: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. Overall design: We used ATAC-seq to compare chromatin accessibility in 3 different tissues and to compare the accessibility of the enhancer in WT and mutant animals.

2019-06-01 | GSE125292 | GEO

Functional dissection of regulatory landscapes reveals non-essential and instructive roles of TADs in regulating gene expression [ChIP-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. Overall design: We used ChIP-seq to identify the binding profiles of H3K27ac and CTCF in the limb buds of E12.5 BL6 mice

2019-06-01 | GSE125293 | GEO

Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells.

Project description:Topologically associating domains (TADs) are fundamental elements of the eukaryotic genomic structure. However, recent studies suggest that the insulating complexes, CTCF/cohesin, present at TAD borders in mammals are absent from those in Drosophila melanogaster, raising the possibility that border elements are not conserved among metazoans. Using in situ Hi-C with sub-kb resolution, here we show that the D. melanogaster genome is almost completely partitioned into >4000 TADs, nearly sevenfold more than previously identified. The overwhelming majority of these TADs are demarcated by the insulator complexes, BEAF-32/CP190, or BEAF-32/Chromator, indicating that these proteins may play an analogous role in flies as that of CTCF/cohesin in mammals. Moreover, extended regions previously thought to be unstructured are shown to consist of small contiguous TADs, a property also observed in mammals upon re-examination. Altogether, our work demonstrates that fundamental features associated with the higher-order folding of the genome are conserved from insects to mammals.

| S-EPMC5768742 | BioStudies

Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes.

Project description:Understanding how regulatory sequences interact in the context of chromosomal architecture is a central challenge in biology. Chromosome conformation capture revealed that mammalian chromosomes possess a rich hierarchy of structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs) and sub-TAD contact domains. TADs appear to act as regulatory microenvironments by constraining and segregating regulatory interactions across discrete chromosomal regions. However, it is unclear whether other (or all) folding layers share similar properties, or rather TADs constitute a privileged folding scale with maximal impact on the organization of regulatory interactions. Here, we present a novel algorithm named CaTCH that identifies hierarchical trees of chromosomal domains in Hi-C maps, stratified through their reciprocal physical insulation, which is a single and biologically relevant parameter. By applying CaTCH to published Hi-C data sets, we show that previously reported folding layers appear at different insulation levels. We demonstrate that although no structurally privileged folding level exists, TADs emerge as a functionally privileged scale defined by maximal boundary enrichment in CTCF and maximal cell-type conservation. By measuring transcriptional output in embryonic stem cells and neural precursor cells, we show that the likelihood that genes in a domain are coregulated during differentiation is also maximized at the scale of TADs. Finally, we observe that regulatory sequences occur at genomic locations corresponding to optimized mutual interactions at the same scale. Our analysis suggests that the architectural functionality of TADs arises from the interplay between their ability to partition interactions and the specific genomic position of regulatory sequences.

| S-EPMC5340975 | BioStudies

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.

| S-EPMC3873244 | BioStudies

Making sense of the linear genome, gene function and TADs.

Project description:<h4>Background</h4>Topologically associating domains (TADs) are thought to act as functional units in the genome. TADs co-localise genes and their regulatory elements as well as forming the unit of genome switching between active and inactive compartments. This has led to the speculation that genes which are required for similar processes may fall within the same TADs, allowing them to share regulatory programs and efficiently switch between chromatin compartments. However, evidence to link genes within TADs to the same regulatory program is limited.<h4>Results</h4>We investigated the functional similarity of genes which fall within the same TAD. To do this we developed a TAD randomisation algorithm to generate sets of "random TADs" to act as null distributions. We found that while pairs of paralogous genes are enriched in TADs overall, they are largely depleted in TADs with CCCTC-binding factor (CTCF) ChIP-seq peaks at both boundaries. By assessing gene constraint as a proxy for functional importance we found that genes which singly occupy a TAD have greater functional importance than genes which share a TAD, and these genes are enriched for developmental processes. We found little evidence that pairs of genes in CTCF bound TADs are more likely to be co-expressed or share functional annotations than can be explained by their linear proximity alone.<h4>Conclusions</h4>These results suggest that algorithmically defined TADs consist of two functionally different groups, those which are bound by CTCF and those which are not. We detected no association between genes sharing the same CTCF TADs and increased co-expression or functional similarity, other than that explained by linear genome proximity. We do, however, find that functionally important genes are more likely to fall within a TAD on their own suggesting that TADs play an important role in the insulation of these genes.

| S-EPMC8800309 | BioStudies

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