Simultaneous single-cell three-dimensional genome and gene expression profiling uncovers dynamic enhancer connectivity underlying olfactory receptor choice

Nature Methods, Journal Year: 2024, Volume and Issue: 21(6), P. 974 - 982

Published: April 15, 2024

Abstract The simultaneous measurement of three-dimensional (3D) genome structure and gene expression individual cells is critical for understanding a genome’s structure–function relationship, yet this challenging existing methods. Here we present ‘Linking mRNA to Chromatin Architecture (LiMCA)’, which jointly profiles the 3D transcriptome with exceptional sensitivity from low-input materials. Combining LiMCA our high-resolution scATAC-seq assay, METATAC, successfully characterized chromatin accessibility, as well paired structures information, developing olfactory sensory neurons. We expanded repertoire known receptor (OR) enhancers discovered unexpected rules their dynamics: OR genes are most accessible during early differentiation. Furthermore, revealed dynamic spatial relationship between ORs behind stepwise expression. These findings offer valuable insights into how connectivity dynamically orchestrate ‘one neuron–one receptor’ selection process.

Language: Английский

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Principles of long-range gene regulation

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 91, P. 102323 - 102323

Published: Feb. 13, 2025

Transcription from gene promoters occurs in specific spatiotemporal patterns multicellular organisms, controlled by genomic regulatory elements. The communication between a element and promoter requires certain degree of physical proximity them; hence, most regulation locally the genome. However, recent discoveries have revealed long-range strategies that enhance interactions elements overcoming distances them linear These new findings challenge traditional view how expression are controlled. This review examines recently reported Drosophila mammals, offering insights into their mechanisms evolution.

Language: Английский

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Tuning cohesin trajectories enables differential readout of the Pcdhα cluster across neurons

Science, Journal Year: 2024, Volume and Issue: 385(6707)

Published: July 25, 2024

Expression of Protocadherin (Pcdh) genes is critical to the generation neuron identity and wiring nervous system. Pcdhα are arranged in clusters exhibit a range expression profiles, from stochastic deterministic. Because promoters have high sequence share distal enhancers, how distinct neurons choose which gene express remains unclear. We show that interplay between multiple epigenetics, genome folding orchestrates differential readouts locus across neurons. The probability promoter choice depends on enhancer/promoter encounters catalyzed by cohesin, whose extrusion trajectories determine likelihood an individual can "escape" heterochromatin-mediated silencing. propose tunable locus-specific regulatory elements cell type-specific cohesin activity underlie cellular diversity Pcdh genes.

Language: Английский

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Genomic snowflakes: how the uniqueness of DNA folding allows us to smell the chemical universe

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102329 - 102329

Published: March 18, 2025

Language: Английский

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Transcriptional priming and chromatin regulation during stochastic cell fate specification

Philosophical Transactions of the Royal Society B Biological Sciences, Journal Year: 2024, Volume and Issue: 379(1900)

Published: March 4, 2024

Stochastic cell fate specification, in which a chooses between two or more fates with set probability, diversifies subtypes development. Although this is vital process across species, common mechanism for these decisions remains elusive. This review examines well-characterized stochastic to identify commonalities their developmental programmes. In the fly eye, of R7 photoreceptors are specified by ON/OFF expression transcription factor, spineless . mouse olfactory system, sensory neurons (OSNs) randomly select express one copy an receptor (OR) gene out pool 2800 alleles. Despite differences systems, both choices rely on dynamic interplay transcriptional priming, chromatin regulation and terminal expression. The coupling modifications primes loci undifferentiated neurons, enabling later during differentiation. Here, we compare mechanisms, examine broader implications development posit key challenges moving forward. article part discussion meeting issue ‘Causes consequences processes disease’.

Language: Английский

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Enhancer‐dependent gene regulation in space, time, and malignancies

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Control of cell-type-specific gene activation requires the coordinated activity distal regulatory elements, including enhancers, whose inputs must be temporally integrated. Dysregulation this capacity, such as aberrant usage can result in malignant transformation cells. In review, we provide an overview our current understanding enhancer-driven regulation and discuss how may integrated across time, followed by epigenetic structural alterations enhancers cancers.

Language: Английский

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Evolution of vertebrate olfactory receptor repertoires and their function

Current Opinion in Behavioral Sciences, Journal Year: 2025, Volume and Issue: 61, P. 101483 - 101483

Published: Feb. 1, 2025

Language: Английский

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3D spatial transcriptomics reveals the molecular domain structure of the mouse olfactory bulb

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

A core organizing principle of the vertebrate brain is its symmetry along multiple axes. However, structure these axes, and precision with which neurons, circuit modules, regions align to them, remain poorly understood. Here, we used 3D spatial transcriptomics reconstruct anatomical molecular organization mouse olfactory bulb. We mapped positions nearly one thousand molecularly distinct glomeruli, structural functional units odor processing, revealing highly symmetric across hemispheres. Within each bulb, defined a curved axis that divides pairs sister glomeruli. Gene expression programs in sensory neurons predicted glomerular position near-glomerular resolution. was disrupted deeper layer mitral granule cells, suggesting reorganization bulb output pathways. Our findings provide first comprehensive map domain

Language: Английский

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Reorganization of the heterochromatin-associated gene-dense subcompartment in early neuronal development

Biology Open, Journal Year: 2025, Volume and Issue: 14(5)

Published: May 12, 2025

ABSTRACT The 3D organization of the genome has emerged as an important regulator cellular development. Post-mitotic neurons undergo conserved changes in organization, such inward radial repositioning heterochromatin-rich chromosomes they differentiate. Additionally, transcriptionally active but heterochromatin-associated gene-dense (hGD) regions significantly strengthen their long-distance interactions during cerebellar However, specific developmental stages which these nuclear take place have remained poorly defined. Here, we report that hGD relocalize toward interior and chromosomal immature granule transition from cell migration to subsequent neuronal differentiation. During this period, genomic are coordinately repositioned nucleus alongside physically tethered heterochromatic chromocenters. Despite major subcompartment remains distinct other or repressive bodies, including chromocenters, throughout Notably, appear be independent transcriptional occur neuron Together, our results provide insights into timing structural post-mitotic neurons.

Language: Английский

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Solid phase transitions as a solution to the genome folding paradox

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: May 14, 2025

Language: Английский

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