A relay velocity model infers cell-dependent RNA velocity

Li, Shengyu; Zhang, Pengzhi; Chen, Weiqing; Ye, Lingqun; Brannan, Kristopher W.; Le, Nhat-Tu; Abe, Jun‐ichi; Cooke, John P.; Wang, Guangyu

doi:10.1038/s41587-023-01728-5

Cited by 35 publications

(21 citation statements)

References 53 publications

(93 reference statements)

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“…To further understand the phenotypic transition of SMCs, we performed RNA velocity analysis using cellDancer 27 (Figure 2C and 2D). The RNA velocity estimated the 2 directions of cell transition: from contractile toward migration/inflammatory phenotype and from contractile/ inflammatory toward other cell types (mostly macrophages; Figure 2C).…”

Section: Progressive Reduction Of Contractile Genes and Induction Of ...mentioning

confidence: 99%

Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

Chakraborty

Zhang

et al. 2023

Circulation

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BACKGROUND: Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified. METHODS: We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II–induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis. RESULTS: Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix–producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and contractile gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting –/– mice, the aortic stress–induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues. CONCLUSIONS: Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.

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Section: Progressive Reduction Of Contractile Genes and Induction Of ...mentioning

confidence: 99%

Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

Chakraborty

Zhang

et al. 2023

Circulation

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“…For further research in the future, we need to combine proteomics to evaluate protein velocity and even combine epigenomics with chromatin velocity to understand the regulation mechanism of the cell cycle more comprehensively. More broadly, when coupled with remarkable advances in singlecell approaches, including multi-velocity, [89] construction of vector fields, [36] as well as spatial multi-omics, [90] we will enable a deeper, quantitative understanding of the spatiotemporally un-derlying mechanism of the cell cycle and other biological systems via nonequilibrium dynamics and thermodynamics to help prevent various diseases, including cancer and neurodegeneration, and open up new possibilities for precision medicine.…”

Section: Discussionmentioning

confidence: 99%

Quantifying Landscape‐Flux via Single‐Cell Transcriptomics Uncovers the Underlying Mechanism of Cell Cycle

Zhu,

Wang

2024

Advanced Science

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Recent developments in single‐cell sequencing technology enable the acquisition of entire transcriptome data. Understanding the underlying mechanism and identifying the driving force of transcriptional regulation governing cell function directly from these data remains challenging. This study reconstructs a continuous vector field of the cell cycle based on discrete single‐cell RNA velocity to quantify the single‐cell global nonequilibrium dynamic landscape‐flux. It reveals that large fluctuations disrupt the global landscape and genetic perturbations alter landscape‐flux, thus identifying key genes in maintaining cell cycle dynamics and predicting associated functional effects. Additionally, it quantifies the fundamental energy cost of the cell cycle initiation and unveils that sustaining the cell cycle requires curl flux and dissipation to maintain the oscillatory phase coherence. This study enables the inference of the cell cycle gene regulatory networks directly from the single‐cell transcriptomic data, including the feedback mechanisms and interaction intensity. This provides a golden opportunity to experimentally verify the landscape‐flux theory and also obtain its associated quantifications. It also offers a unique framework for combining the landscape‐flux theory and single‐cell high‐through sequencing experiments for understanding the underlying mechanisms of the cell cycle and can be extended to other nonequilibrium biological processes, such as differentiation development and disease pathogenesis.

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“…For further research in the future, we need to combine proteomics to evaluate protein velocity and even combine epigenomics with chromatin velocity to understand the regulation mechanism of the cell cycle more comprehensively. More broadly, when coupled with remarkable advances in single-cell approaches, including multi-velocity (83), construction of vector fields (35), as well as spatial multi-omics (84), we will enable a deeper, quantitative understanding of the spatiotemporally underlying mechanism of the cell cycle and other biological systems via non-equilibrium dynamics and thermodynamics to help prevent various diseases, including cancer and neurodegeneration, and open up new possibilities for precision medicine.…”

Section: Discussionmentioning

confidence: 99%

Quantifying landscape-flux via single-cell transcriptomics uncovers the underlying mechanism of cell cycle

Zhu

Wang

2023

Preprint

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Recent developments of single-cell sequencing technology enabling acquisition of the whole transcriptome data. To uncover the underlying mechanism of cell cycle function from such data, we reconstruct a continuous vector field based on the discrete single-cell RNA velocity to quantify the global non-equilibrium dynamical landscape and flux. We reveal that biological noise can make the global landscape more complex and less predictable. Genetic perturbations alter landscape-flux, thus identify key genes in maintaining cell cycle dynamics and predict the associated effects on cell cycle behaviour. Cell cycle initiation costs energy and sustaining cell cycle requires dissipation to increase oscillatory phase coherence. This approach enables the inference of cell cycle gene regulatory networks directly from single-cell transcriptomic data, including feedback mechanisms. Our study provides a new framework with insights into cell cycle regulation from single-cell transcriptome data and can be extended to other biological processes, such as differentiation-development and disease pathogenesis

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A relay velocity model infers cell-dependent RNA velocity

Cited by 35 publications

References 53 publications

Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

Quantifying Landscape‐Flux via Single‐Cell Transcriptomics Uncovers the Underlying Mechanism of Cell Cycle

Quantifying landscape-flux via single-cell transcriptomics uncovers the underlying mechanism of cell cycle

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