Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA324819 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3647790.fastq.gz | Fastqsanger.gz | |||
| SRR3647791.fastq.gz | Fastqsanger.gz | |||
| SRR3647792.fastq.gz | Fastqsanger.gz | |||
| SRR3647793.fastq.gz | Fastqsanger.gz |
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Project description:The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow certain level of physical crosstalk across regulatory domains, which is at odds with the highly specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites synergistically foster the robust insulation of regulatory domains. Firstly, we found that the TADs containing developmental genes have distinctive features, including the sequential organization of developmental genes and CTCF clusters near TAD boundaries. Most importantly, by genetically dissecting representative loci in mouse embryonic stem cells, we showed that developmental genes and CTCF sites synergistically strengthened the insulation capacity of nearby boundaries through different mechanisms. Namely, while CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the specificity of gene regulation, which in turn might help interpreting the pathological consequences of certain structural variants.
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Project description:The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow certain level of physical crosstalk across regulatory domains, which is at odds with the highly specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites synergistically foster the robust insulation of regulatory domains. Firstly, we found that the TADs containing developmental genes have distinctive features, including the sequential organization of developmental genes and CTCF clusters near TAD boundaries. Most importantly, by genetically dissecting representative loci in mouse embryonic stem cells, we showed that developmental genes and CTCF sites synergistically strengthened the insulation capacity of nearby boundaries through different mechanisms. Namely, while CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the specificity of gene regulation, which in turn might help interpreting the pathological consequences of certain structural variants.
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Project description:Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification involved in the formation of constitutive heterochromatin, gene repression and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin compartments to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the role of SETDB1 in stimulus-inducible gene expression in macrophages, we unexpectedly found that upon SETDB1 depletion, loss of H3K9me3 in active compartments was associated with increased recruitment of CTCF to >1,600 DNA-binding motifs contained within SINE-B2 repeats, a previously unidentified target of SETDB1-mediated repression. CTCF is an essential regulator of chromatin folding that restrains DNA looping by cohesin, thus creating boundaries among adjacent topological domains. Increased CTCF binding to SINE-B2 repeats generated novel boundaries within topological domains containing lipopolysaccharide-inducible genes, correlating with their impaired regulation in response to stimulation. These data indicate a role of H3K9me3 in restraining genomic distribution and activity of CTCF, with impact on chromatin organization and gene regulation.
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Project description:Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification involved in the formation of constitutive heterochromatin, gene repression and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin compartments to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the role of SETDB1 in stimulus-inducible gene expression in macrophages, we unexpectedly found that upon SETDB1 depletion, loss of H3K9me3 in active compartments was associated with increased recruitment of CTCF to >1,600 DNA-binding motifs contained within SINE-B2 repeats, a previously unidentified target of SETDB1-mediated repression. CTCF is an essential regulator of chromatin folding that restrains DNA looping by cohesin, thus creating boundaries among adjacent topological domains. Increased CTCF binding to SINE-B2 repeats generated novel boundaries within topological domains containing lipopolysaccharide-inducible genes, correlating with their impaired regulation in response to stimulation. These data indicate a role of H3K9me3 in restraining genomic distribution and activity of CTCF, with impact on chromatin organization and gene regulation.
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Project description:Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification involved in the formation of constitutive heterochromatin, gene repression and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin compartments to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the role of SETDB1 in stimulus-inducible gene expression in macrophages, we unexpectedly found that upon SETDB1 depletion, loss of H3K9me3 in active compartments was associated with increased recruitment of CTCF to >1,600 DNA-binding motifs contained within SINE-B2 repeats, a previously unidentified target of SETDB1-mediated repression. CTCF is an essential regulator of chromatin folding that restrains DNA looping by cohesin, thus creating boundaries among adjacent topological domains. Increased CTCF binding to SINE-B2 repeats generated novel boundaries within topological domains containing lipopolysaccharide-inducible genes, correlating with their impaired regulation in response to stimulation. These data indicate a role of H3K9me3 in restraining genomic distribution and activity of CTCF, with impact on chromatin organization and gene regulation.
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Project description:Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification involved in the formation of constitutive heterochromatin, gene repression and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin compartments to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the role of SETDB1 in stimulus-inducible gene expression in macrophages, we unexpectedly found that upon SETDB1 depletion, loss of H3K9me3 in active compartments was associated with increased recruitment of CTCF to >1,600 DNA-binding motifs contained within SINE-B2 repeats, a previously unidentified target of SETDB1-mediated repression. CTCF is an essential regulator of chromatin folding that restrains DNA looping by cohesin, thus creating boundaries among adjacent topological domains. Increased CTCF binding to SINE-B2 repeats generated novel boundaries within topological domains containing lipopolysaccharide-inducible genes, correlating with their impaired regulation in response to stimulation. These data indicate a role of H3K9me3 in restraining genomic distribution and activity of CTCF, with impact on chromatin organization and gene regulation.
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Project description:Understanding the topological configurations of chromatin can reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3-D interactions that undergo marked reorganization at the sub-Mb scale during differentiation. Distinct combinations of CTCF, Mediator, and cohesin show widespread enrichment in architecture at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant sub-domains. Conversely, Mediator/cohesin together with pioneer factors bridge short-range enhancer-promoter interactions within and between larger sub-domains. Knockdown of Smc1 or Med12 in ES cells results in disruption of spatial architecture and down-regulation of genes found in cohesin-mediated interactions. We conclude that cell type-specific chromatin organization occurs at the sub-Mb scale and that architectural proteins shape the genome in hierarchical length scales. Analysis of higher-order chromatin chromatin architecture in mouse ES cells and ES-derived NPCs. Analysis of CTCF and Smc1 occupied sites in ES-derived NPCs.
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Project description:The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is limited. Here we present high-resolution analyses of chromosomal organization in pluripotent and differentiated human and murine cell types determined using the Hi-C technique. We find that the mammalian genome is composed of over 1000 topological domains, which are stable among different cell types and highly conserved across species. These megabase-long genomic structures, defined by prominent local chromatin interactions and separated by narrow boundary regions, likely function to restrict regulatory interactions between cis-acting elements and limit the spreading of heterochromatin during cellular differentiation. Interestingly, the boundaries are enriched not only for binding sites of the insulator protein CTCF, but also for promoters of house keeping genes, supporting a role for both CTCF and housekeeping genes in the establishment or maintenance of the topological domains. Hi-C experiment were conducted in mESC, hESC and IMR90 cells
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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.
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