Cis-regulatory chromatin contacts form de novo in the absence of loop extrusion

Опубликована: Янв. 13, 2025

SUMMARY NIPBL promotes chromatin loop extrusion by the cohesin complex until it stalls at convergently oriented CTCF sites, leading to formation of structural loops. However, what extent contributes establishment vs maintenance cis -regulatory element (CRE) connectivity is poorly understood. Here, we explored de novo folding patterns mitosis-to-G1-phase transition upon acute loss. depletion primarily impaired cohesin-mediated loops with dependence being proportional length. In contrast, majority CRE were established independently regardless slowed re-formation weak enhancers. Transcription genes NIPBL-independent anchors was activated normally in absence NIPBL. sum, most regulatory contacts and gene transcription following mitotic exit independent extrusion.

Язык: Английский

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Long-range enhancer-controlled genes are hypersensitive to regulatory factor perturbations

Cell Genomics, Год журнала: 2025, Номер unknown, С. 100778 - 100778

Опубликована: Фев. 1, 2025

Cell-type-specific gene activation is regulated by enhancers, sometimes located at large genomic distances from target promoters. Whether distal enhancers require specific factors to orchestrate regulation remains unclear. Here, we used enhancer distance-controlled reporter screens find candidate factors. We depleted them and employed activity-by-contact predictions genome-wide classify genes based on distance. Predicted typically control tissue-restricted often are strong enhancers. cohesin, but also mediator, most specifically required for long-range activation, with cohesin repressing short-range prioritizing over proximal HBB competing shared Long-range controlled sensitive perturbations of other regulatory proteins BET inhibitor JQ1, this being more a consequence their distinct features than Our work predicts that lengthening intervening sequences can help limit the expression specialized cells optimal trans-factor environments.

Язык: Английский

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Post-mitotic transcriptional activation and 3D regulatory interactions show locus- and differentiation-specific sensitivity to cohesin depletion

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Abstract Prior studies showed that structural loops collapse upon acute cohesin depletion, while regulatory enhancer-promoter (E-P) largely persist, consistent with minimal transcriptional changes. However, these studies, conducted in asynchronous cells, could not resolve whether is required for the establishment of interactions and activation during cell division or state transitions. To address this gap, we degraded RAD21, a core subunit, naïve mouse embryonic stem cells (ESCs) transitioning from mitosis to G1 either self-renewal condition differentiation toward formative pluripotency. Although most failed be re-established without cohesin, about 35% reformed at normal higher frequencies. Cohesin-independent characteristics strong active enhancers promoters significant association H3K27ac mitotic bookmarks. inhibition CBP/p300 exit did impact cohesin-independent interactions, suggesting presence complex compensatory mechanisms. At level, depletion induced only minor changes, supporting post-mitotic reactivation independent cohesin. The few genes impaired were directly bound by RAD21 their promoters, engaged many loops, located within strongly insulated TADs low gene density. Importantly, degrading M-to-G1 transition EpiLC signals revealed larger group susceptible genes, including key signature transcription factors. Impaired was partly due failure establish de novo EpiLC-specific absence These experiments locus-specific context-specific dependencies between E-P transcription.

Язык: Английский

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Distance matters: How protein regulators facilitate enhancer-promoter interactions and transcription

Cell Genomics, Год журнала: 2025, Номер 5(3), С. 100817 - 100817

Опубликована: Март 1, 2025

Cohesin, transcription factors (TFs), and mediator complex components regulate gene expression partly by regulating enhancer-promoter (E-P) communication. A new study combined E-P distance-controlled reporter screens with the inhibition or degradation of regulatory proteins uncovered a distance-dependent effect across cohesin, TFs, components.

Язык: Английский

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Is Enhancer Function Driven by Protein–Protein Interactions? From Bacteria to Leukemia

BioEssays, Год журнала: 2025, Номер unknown

Опубликована: Апрель 8, 2025

ABSTRACT The precise regulation of the transcription genes is essential for normal development and maintenance life. Aberrant gene expression changes drive many human diseases. Despite this, we still do not completely understand how controlled in living systems. Enhancers are key regulatory elements that enable cells to specifically activate response environmental cues, or a stage tissue‐specific manner. Any model enhancer activity needs answer two main questions: (1) enhancers able identify act on specific (2) influence transcription. To address these points, first outline some basic principles can be established from simpler prokaryotic systems, then discuss recent work aberrant leukemia. We argue highly protein–protein interactions driver enhancer‐promoter proximity, allowing enhancer‐bound factors directly RNA polymerase

Язык: Английский

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3D genome folding in epigenetic regulation and cellular memory

Trends in Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

The 3D folding of the genome is tightly linked to its epigenetic state which maintains gene expression programmes. Although relationship between and organisation highly context dependent, emerging as a novel layer reinforce stabilise transcriptional states. Whether regulatory information carried in could be transmitted through mitosis an area active investigation. In this review, we discuss nuclear organisation, well interplay regulation folding. We also consider architectural remodelling nuclei cells enter exit mitosis, evaluate potential contribute cellular memory.

Язык: Английский

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Genomic and Epigenomic Plasticity in the Hypoxic Environment

DNA, Год журнала: 2025, Номер 5(2), С. 22 - 22

Опубликована: Май 4, 2025

Our genome has evolved a complex network of information designed to precisely regulate gene transcription. Commonly known as cis-regulatory elements, they represent those parts DNA that are highly sensitive environmental changes in the form associated multi-protein complexes. Oxygen levels an important factor influencing range cellular activities, including cell survival. To respond oxygen levels, cells have developed efficient and precise system for regulating expression. Cis-regulatory elements key hubs this response control activation transcriptional hypoxia. In review, we will discuss genomic epigenomic structures modulated by activity adaptations variations O2 availability.

Язык: Английский

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Solid phase transitions as a solution to the genome folding paradox

Nature, Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Язык: Английский

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The dance of promoters and enhancers in gene regulation: fast or slow, entwined or distant?

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 169223 - 169223

Опубликована: Май 1, 2025

Язык: Английский

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Genetic factors mediating long-range enhancer–promoter communication in mammalian development

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 90, С. 102282 - 102282

Опубликована: Ноя. 22, 2024

Язык: Английский

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