Conserved Cis-Acting Range Extender Element Mediates Extreme Long-Range Enhancer Activity in Mammals

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 27, 2024

While most mammalian enhancers regulate their cognate promoters over moderate distances of tens kilobases (kb), some act in the megabase range. The sequence features enabling such extreme-distance enhancer-promoter interactions remain elusive. Here, we used

Язык: Английский

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Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 9, 2024

Abstract Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant therapy, inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this its effects. Here, we compile a cohort 28 patient-derived glioblastoma stem cell-like lines (GSCs) reflect properties their tumor-of-origin; six were primary-relapse tumor pairs from same patient. We generate analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data all GSCs systematically map thousands standalone complex structural variants (SVs) multitude neoloops arising as result. By combining Hi-C, histone modification, gene expression with chromatin folding simulations, explain pervasive, uneven, idiosyncratic occurrence sustains tumor-specific programs via formation new enhancer-promoter contacts. also show even moderately recurrent can relate patient-specific vulnerabilities. Together, our provide resource for dissecting biology heterogeneity, well informing therapeutic approaches.

Язык: Английский

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Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation

Molecular Cell, Год журнала: 2024, Номер 84(7), С. 1365 - 1376.e7

Опубликована: Март 6, 2024

Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but underlying structures mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth (FGF) oncogenes disrupted DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The contains an array of CTCF sites enforce adjacent TADs, one containing FGF genes other ANO1 its putative enhancers, which are specifically active GIST likely cell origin. We show coordinate disruption four motifs fuses allows enhancer to contact FGF3, causes robust induction. High-resolution micro-C maps reveal specific between transcription initiation FGF3 promoter quantitatively scales with induction such modest changes frequency result strong expression, consistent causal relationship.

Язык: Английский

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Exploring the interplay between enhancer–promoter interactions and transcription

Current Opinion in Genetics & Development, Год журнала: 2025, Номер 90, С. 102303 - 102303

Опубликована: Янв. 14, 2025

Enhancers in metazoan genomes are known to activate their target genes across both short and long genomic distances. Recent advances chromosome conformation capture assays single-cell imaging have shed light on the underlying chromatin contacts dynamics. Yet relationship between 3D physical enhancer-promoter (E-P) interactions transcriptional activation remains unresolved. In this brief review, we discuss recent studies exploring scales: from developmental stages minutes surrounding tissue level single-allele subcellular We how seemingly contradictory observations might be reconciled contribute a refined causal E-P transcription, with mutual influences.

Язык: Английский

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Bridging spatial and temporal scales of developmental gene regulation

Current Opinion in Genetics & Development, Год журнала: 2025, Номер 92, С. 102328 - 102328

Опубликована: Март 12, 2025

The development of multicellular organisms relies on the precise coordination molecular events across multiple spatial and temporal scales. Understanding how information flows from interactions to cellular processes tissue organization during is crucial for explaining remarkable reproducibility complex organisms. This review explores chromatin-encoded transduced localized transcriptional global gene expression patterns, highlighting challenge bridging these We discuss recent experimental findings theoretical frameworks, emphasizing polymer physics as a tool describing relationship between chromatin structure dynamics By integrating perspectives, we aim clarify regulation coordinated levels biological suggest strategies future approaches.

Язык: Английский

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Hypoxia-induced phase separation of ZHX2 alters chromatin looping to drive cancer metastasis

Molecular Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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Mechanisms of Interaction between Enhancers and Promoters in Three Drosophila Model Systems

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(3), С. 2855 - 2855

Опубликована: Фев. 2, 2023

In higher eukaryotes, the regulation of developmental gene expression is determined by enhancers, which are often located at a large distance from promoters they regulate. Therefore, architecture chromosomes and mechanisms that determine functional interaction between enhancers decisive importance in development organisms. Mammals model animal Drosophila have homologous key architectural proteins similar organization chromosome architecture. This review describes current progress understanding formation long-range interactions three well-studied regulatory loci Drosophila.

Язык: Английский

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Recent progress and challenges in single-cell imaging of enhancer–promoter interaction

Current Opinion in Genetics & Development, Год журнала: 2023, Номер 79, С. 102023 - 102023

Опубликована: Фев. 26, 2023

Язык: Английский

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scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells

Nature Methods, Год журнала: 2023, Номер 20(10), С. 1493 - 1505

Опубликована: Авг. 28, 2023

Язык: Английский

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Synergy between cis-regulatory elements can render cohesin dispensable for distal enhancer function

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 4, 2024

Abstract Enhancers are critical genetic elements controlling transcription from promoters, but the mechanisms by which they convey regulatory information across large genomic distances remain elusive. Here, we engineered pluripotent stem cells in cohesin loop extrusion can be inducibly disrupted without causing confounding cell cycle defects. While evident, transcriptional dysregulation was cell-type specific, and not all loci with distal enhancers depend equally on extrusion. Using comparative genome editing, demonstrate that enhancer-promoter communication as little 20 kilobases rely cohesin. However, promoter-proximal support long-range, cohesin-independent enhancer action – either upon disabling or strong CTCF insulators. Finally, dynamics emergence of new embryonic types response to differentiation cues remained largely robust disrupting Beyond establishing novel experimental strategies study functions biology, our work provides mechanistic insight accounting for both type- context-specificity.

Язык: Английский

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