SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks

Nature Methods, Journal Year: 2023, Volume and Issue: 20(9), P. 1355 - 1367

Published: July 13, 2023

Abstract Joint profiling of chromatin accessibility and gene expression in individual cells provides an opportunity to decipher enhancer-driven regulatory networks (GRNs). Here we present a method for the inference GRNs, called SCENIC+. SCENIC+ predicts genomic enhancers along with candidate upstream transcription factors (TFs) links these target genes. To improve both recall precision TF identification, curated clustered motif collection more than 30,000 motifs. We benchmarked on diverse datasets from different species, including human peripheral blood mononuclear cells, ENCODE cell lines, melanoma states Drosophila retinal development. Next, exploit predictions study conserved TFs, GRNs between mouse types cerebral cortex. Finally, use dynamics regulation differentiation trajectories effect perturbations state. is available at scenicplus.readthedocs.io .

Language: Английский

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Deciphering the multi-scale, quantitative cis-regulatory code

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(3), P. 373 - 392

Published: Jan. 23, 2023

Uncovering the cis-regulatory code that governs when and how much each gene is transcribed in a given genome cellular state remains central goal of biology. Here, we discuss major layers regulation influence transcriptional outputs are encoded by DNA sequence context. We first transcription factors bind specific sequences dosage-dependent cooperative manner then proceed to cofactors facilitate factor function mediate activity modular elements such as enhancers, silencers, promoters. consider complex poorly understood interplay these diverse within regulatory landscapes its relationships with chromatin states nuclear organization. propose mechanistically informed, quantitative model integrates multiple will be key ultimately cracking code.

Language: Английский

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Linking genome structures to functions by simultaneous single-cell Hi-C and RNA-seq

Science, Journal Year: 2023, Volume and Issue: 380(6649), P. 1070 - 1076

Published: June 8, 2023

Much progress has been made recently in single-cell chromosome conformation capture technologies. However, a method that allows simultaneous profiling of chromatin architecture and gene expression not reported. Here, we developed an assay named "Hi-C RNA-seq employed simultaneously" (HiRES) performed it on thousands single cells from developing mouse embryos. Single-cell three-dimensional genome structures, despite being heavily determined by the cell cycle developmental stages, gradually diverged type-specific manner as development progressed. By comparing pseudotemporal dynamics interactions with expression, found widespread rewiring occurred before transcription activation. Our results demonstrate establishment specific is tightly related to transcriptional control functions during lineage specification.

Language: Английский

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Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(15), P. 2624 - 2640

Published: July 6, 2023

Language: Английский

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TADs: Dynamic structures to create stable regulatory functions

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 81, P. 102622 - 102622

Published: June 9, 2023

Language: Английский

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Real-time single-molecule imaging of transcriptional regulatory networks in living cells

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(4), P. 272 - 285

Published: Jan. 9, 2024

Language: Английский

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Resolving the three-dimensional interactome of human accelerated regions during human and chimpanzee neurodevelopment

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

Published: Jan. 1, 2025

Language: Английский

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Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries

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

Published: Sept. 12, 2023

Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites the CTCF insulator protein. Here we determine how this clustering contributes to blocking extrusion and insulation between TADs. We identify enrichment three features at strong boundaries, strongly bound closely spaced peaks, a further DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells normal perturbed binding, establish individual contribute but an incomplete manner. When clustered, thus create stepwise neighboring Based on results, propose model whereby multiple instances temporal

Language: Английский

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Size limits the sensitivity of kinetic schemes

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

Published: March 8, 2023

Abstract Living things benefit from exquisite molecular sensitivity in many of their key processes, including DNA replication, transcription and translation, chemical sensing, morphogenesis. At thermodynamic equilibrium, the basic biophysical mechanism for is cooperative binding, which it can be shown that Hill coefficient, a measure, cannot exceed number binding sites. Generalizing this fact, we find any kinetic scheme, at or away very simple structural quantity, size support perturbation, always limits effective coefficient. We show how bound sheds light on unifies diverse mechanisms, proofreading nonequilibrium Monod-Wyman-Changeux (MWC) model proposed E. coli flagellar motor switch, representing each case simple, precise bridge between experimental observations models write down. In pursuit mechanisms saturate bound, mechanism, nested hysteresis, with exponential sites, implications our understanding gene regulation function biomolecular condensates.

Language: Английский

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The enhancer landscape predetermines the skeletal regeneration capacity of stromal cells

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(688)

Published: March 22, 2023

Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental clinical studies, broad application of therapeutics is not yet emerging. A major challenge the functional diversity available sources. Here, we investigated regenerative potential clinically relevant human from bone marrow (BMSCs), white adipose tissue, umbilical cord compared with mature chondrocytes skin fibroblasts in vitro vivo. Although all types could express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs that fully regenerated critical-size femoral defects after transplantation into mice. We identified type–specific epigenetic landscapes as underlying molecular mechanism controlling transcriptional differentiation networks. Binding sites commonly expressed enhancer promoter regions ossification-related genes, including Runt bZIP families, were accessible but extraskeletal cells. This suggests an epigenetically predetermined depending on origin allows common trigger distinct organ-specific programs, facilitating forward selection regeneration-competent Last, demonstrate viable initiated defect healing through secretion osteopontin contributed transient mineralized hard callus formation immunodeficient mice, which was eventually replaced by murine recipient during final remodeling.

Language: Английский

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