3D enhancer-promoter interactions and multi-connected hubs: Organizational principles and functional roles

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112068 - 112068

Published: April 1, 2023

The spatiotemporal control of gene expression is dependent on the activity cis-acting regulatory sequences, called enhancers, which regulate target genes over variable genomic distances and, often, by skipping intermediate promoters, suggesting mechanisms that enhancer-promoter communication. Recent genomics and imaging technologies have revealed highly complex interaction networks, whereas advanced functional studies started interrogating forces behind physical communication among multiple enhancers promoters. In this review, we first summarize our current understanding factors involved in communication, with a particular focus recent papers new layers complexities to old questions. second part subset connected "hubs" discuss their potential functions signal integration regulation, as well putative might determine dynamics assembly.

Language: Английский

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Chromatin alternates between A and B compartments at kilobase scale for subgenic organization

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 6, 2023

Abstract Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops generally studied a finer scale, the impact looping on proximal interactions remains enigmatic. Here, we critically examine nuclear and loop-proximal using combination in situ Hi-C unparalleled depth, algorithm development, biophysical modeling. Producing large map with 33 billion contacts conjunction an for performing principal component analysis sparse, super massive matrices (POSSUMM), resolve to 500 bp. Our results demonstrate that essentially all active promoters distal enhancers localize A compartment, even when flanking sequences do not. Furthermore, find TSS TTS paused genes often segregated into separate compartments. We then identify diffuse radiate from loop anchors, which correlate strong enhancer-promoter transcription. also these depend CTCF’s RNA binding domains. In this work, fine-scale organization consistent revised model more precise than commonly thought while protracted.

Language: Английский

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Enhancer–promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(2), P. 280 - 290

Published: Jan. 30, 2023

Language: Английский

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Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(7), P. 574 - 591

Published: Feb. 27, 2024

Language: Английский

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The Mediator complex regulates enhancer-promoter interactions

Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(7), P. 991 - 1000

Published: July 1, 2023

Abstract Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target promoters. However, the molecular mechanisms by which interactions promoters are formed not well understood. Here, we investigate function of Mediator complex in regulation enhancer-promoter interactions, combining rapid protein depletion high-resolution MNase-based chromosome conformation capture approaches. We show that leads to reduced interaction frequencies, associated with a strong decrease expression. In addition, find increased CTCF-binding sites upon depletion. These changes chromatin architecture redistribution Cohesin on reduction occupancy at enhancers. Together, our results indicate complexes contribute provide insights into communication is regulated.

Language: Английский

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Polymer folding through active processes recreates features of genome organization

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(20)

Published: May 8, 2023

From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have measured in the context chromatin motion, which shows spatial correlations enhanced subdiffusion only presence adenosine triphosphate. Moreover, motion varies genomic coordinate, pointing toward a heterogeneous pattern processes along sequence. How do such patterns affect conformation polymer as chromatin? We address this question by combining analytical theory simulations study subjected sequence-dependent correlated forces. Our analysis local increase (larger forces) can cause backbone bend expand, while less segments straighten out condense. further predict modest differences drive compartmentalization consistent observed chromosome capture experiments. show (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead repulsions. Thus, our offers nonequilibrium mechanisms for forming compartments, cannot be distinguished from affinity-based using structural data alone. As first step exploring whether contribute shaping genome conformations, we discuss data-driven approach.

Language: Английский

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The impact of DNA methylation on CTCF-mediated 3D genome organization

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(3), P. 404 - 412

Published: March 1, 2024

Language: Английский

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Multiplex profiling of developmental cis-regulatory elements with quantitative single-cell expression reporters

Nature Methods, Journal Year: 2024, Volume and Issue: 21(6), P. 983 - 993

Published: May 9, 2024

Abstract The inability to scalably and precisely measure the activity of developmental cis -regulatory elements (CREs) in multicellular systems is a bottleneck genomics. Here we develop dual RNA cassette that decouples detection quantification tasks inherent multiplex single-cell reporter assays. resulting measurement expression accurate over multiple orders magnitude, with precision approaching limit set by Poisson counting noise. Together barcode stabilization via circularization, these scalable quantitative reporters provide high-contrast readouts, analogous classic situ assays but entirely from sequencing. Screening >200 regions accessible chromatin vitro model early mammalian development, identify 13 (8 previously uncharacterized) autonomous cell-type-specific CREs. We further demonstrate chimeric CRE pairs generate cognate two-cell-type profiles assess gain- loss-of-function phenotypes variants perturbed transcription factor binding sites. Single-cell can be applied quantitatively characterize native, synthetic CREs at scale, high sensitivity resolution.

Language: Английский

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Nuclear and genome dynamics underlying DNA double-strand break repair

Nature Reviews Molecular Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 17, 2025

Language: Английский

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Chromatin domains in the cell: Phase separation and condensation

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 91, P. 103006 - 103006

Published: Feb. 20, 2025

Language: Английский

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