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Two unrelated distal genes activated by a shared enhancer benefit from localizing inside the same small topological domain (HiC).

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274835 | GEO | 2025/02/19

REPOSITORIES: GEO

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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

2025-02-19 | GSE284650 | GEO

Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression

Project description:To understand how chromatin domains coordinate gene expression, we dissected select genetic elements organizing topology and transcription around the Prdm14 super enhancer in mouse embryonic stem cells. Taking advantage of allelic polymorphisms, we developed methods to sensitively analyze changes in chromatin topology, gene expression, and protein recruitment. We show that enhancer insulation does not strictly rely on loop formation between its flanking boundaries, that the enhancer activates the Slco5a1 gene beyond its prominent domain boundary, and that it recruits cohesin for loop extrusion. Upon boundary inversion, we find that oppositely-oriented CTCF terminates extrusion trajectories but does not stall cohesin, while deleted or mutated CTCF sites allow cohesin to extend its trajectory. Enhancer-mediated gene activation occurs independent of paused loop extrusion near the gene promoter. We expand upon the loop extrusion model to propose that cohesin loading and extrusion trajectories originating at an enhancer contribute to gene activation.

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Essential role of Cp190 in physical and regulatory boundary formation in Drosophila

Project description:Animal genomes fold into contact domains defined by enhanced internal contact frequencies with debated functions in establishing independent gene regulatory domains. A large fraction of contact domains in mammals are formed by stalling of chromosomal loop-extruding cohesin by CTCF at domain boundaries. 90% of domain boundaries in Drosophila form CTCF-independently, and other proteins were proposed to form chromosomal loops with dual functions of segregating promoters from inappropriate regulatory elements and connecting distal regulatory elements to their correct targets. Here, we genetically ablate the ubiquitous boundary-associated factor Cp190 and assess impacts on genome folding and transcriptional regulation in embryos. Our results reveal that Cp190 is a major factor required for contact domain boundary formation and gene insulation in Drosophila.

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Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

Project description:Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role to stimulate transcription initiation and elongation from target gene promoters and a role to recruit cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping, and the activation of distal target genes.

2022-04-08 | GSE180566 | GEO

A cohesin traffic pattern genetically linked to gene regulation [Hi-C]

Project description:Cohesin-mediated loop extrusion folds interphase chromosomes at the ten to hundreds kilobases scale. This process produces structural features such as loops and topologically associating domains. We identify three types of cis-elements that define the chromatin folding landscape generated by loop extrusion. First, CTCF sites form boundaries by stalling extruding cohesin, as shown before. Second, transcription termination sites form boundaries by acting as cohesin unloading sites. RNA polymerase II contributes to boundary formation at transcription termination sites. Third, transcription start sites form boundaries that are mostly independent of cohesin, but are sites where cohesin can pause. Together with cohesin loading at enhancers, and possibly other cis-elements, these loci create a dynamic pattern of cohesin traffic along the genome that guides enhancer-promoter interactions. Disturbing this traffic pattern, by removing CTCF barriers, makes cells sensitive to deletion of genes involved in transcription initiation, such as the SAGA and TFIID complexes, and RNA processing such DEAD-Box RNA helicases. In the absence of CTCF, several of these factors fail to be efficiently recruited to active promoters. We propose that the complex pattern of cohesin movement along chromatin contributes to appropriate promoter-enhancer interactions and localization of transcription and RNA processing factors to active genes.

2022-08-15 | GSE180922 | GEO

A cohesin traffic pattern genetically linked to gene regulation [RNA-Seq]

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A cohesin traffic pattern genetically linked to gene regulation [ChIP-Seq]

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Chromosome structure in Drosophila is determined by boundary pairing not loop extrusion

Project description:Two different models have been proposed to explain how the endpoints of chromatin looped domains (“TADs”) in eukaryotic chromosomes are determined. In the first, a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop (and an unanchored loop). In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of MicroC to analyze how TADs are organized and experimental manipulations of the even skipped TAD boundary, homie, to test the predictions of the “loop-extrusion” and the “boundary-pairing” models. Our findings are incompatible with the loop-extrusion model and instead suggest that the endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their partners, either head-to-head, or head-to-tail, with varying degrees of specificity. Although our experiments do not address how partners find each other, the mechanism is unlikely involve loop extrusion.

2024-04-04 | GSE263229 | GEO

Determinants of chromosome organization: Loop extrusion or boundary:boundary pairing?

Project description:Two different models have been proposed to explain how the endpoints of chromatin looped domains (“TADs”) in eukaryotic chromosomes are determined. In the first a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop (and an unanchored loop). In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of Micro-C to analyze how TADs are organized and experimental manipulations of the even-skipped TAD boundary, homie, to test the predictions of the “loop-extrusion” and the “boundary-pairing” models. Our findings are incompatible with the loop-extrusion model and instead suggest that endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their neighbors, either head-to-head, or head-to-tail.

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