Joint analysis of chromatin accessibility and gene expression in the same single cells reveals cancer-specific regulatory programs DOI Creative Commons
Lei Tang, Jinsong Zhang,

Yanqiu Shao

et al.

Cell Systems, Journal Year: 2025, Volume and Issue: unknown, P. 101266 - 101266

Published: April 1, 2025

Biological analyses conducted at the single-cell scale have revealed profound impacts of heterogeneity and plasticity chromatin states gene expression on physiology cancer. Here, we developed Parallel-seq, a technology for simultaneously measuring accessibility in same single cells. By combining combinatorial cell indexing droplet overloading, Parallel-seq generates high-quality data an ultra-high-throughput fashion cost two orders magnitude lower than alternative technologies (10× Multiome ISSAAC-seq). We applied to 40 lung tumor tumor-adjacent clinical samples obtained over 200,000 joint scATAC-and-scRNA profiles. Leveraging this large dataset, characterized copy-number variations (CNVs) extrachromosomal circular DNA (eccDNA) cells, predicted hundreds thousands cell-type-specific regulatory events, identified enhancer mutations affecting progression. Our highlight Parallel-seq's power investigating epigenetic genetic factors driving cancer development level its utility revealing vulnerable therapeutic targets.

Language: Английский

The technological landscape and applications of single-cell multi-omics DOI Open Access
Alev Baysoy, Zhiliang Bai, Rahul Satija

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(10), P. 695 - 713

Published: June 6, 2023

Language: Английский

Citations

483
SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks DOI Creative Commons
Carmen Bravo González‐Blas, Seppe De Winter, Gert Hulselmans

et al.

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

Citations

314
Pluripotent stem cell-derived model of the post-implantation human embryo DOI Creative Commons
Bailey A. T. Weatherbee, Carlos W. Gantner, Lisa K. Iwamoto-Stohl

et al.

Nature, Journal Year: 2023, Volume and Issue: 622(7983), P. 584 - 593

Published: June 27, 2023

Abstract The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by inability to observe in vivo. Models derived from stem cells are important tools for interrogating developmental events and tissue–tissue crosstalk during these stages 1 . Here we establish a model post-implantation embryo, embryoid, comprising embryonic extraembryonic tissues. We combine two types extraembryonic-like cell generated overexpression transcription factors with wild-type promote their self-organization structures that mimic several aspects embryo. These self-organized aggregates contain pluripotent epiblast-like domain surrounded Our functional studies demonstrate robustly differentiates amnion, mesenchyme primordial germ cell-like response bone protein cues. In addition, identify an inhibitory role SOX17 specification anterior hypoblast-like 2 Modulation subpopulations compartment demonstrates influence differentiation, highlighting crosstalk. conclusion, present modular, tractable, integrated 3 will enable us probe key questions development, critical window which substantial numbers pregnancies fail.

Language: Английский

Citations

145
Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance DOI Creative Commons
Evgenia Salta, Orly Lazarov, Carlos P. Fitzsimons

et al.

Cell stem cell, Journal Year: 2023, Volume and Issue: 30(2), P. 120 - 136

Published: Feb. 1, 2023

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, clinical data critically discuss the multicellular complexity niche relation to pathophysiology. further present roadmap toward better understanding role by probing promises caveats latest technological advancements field addressing conceptual methodological challenges ahead.

Language: Английский

Citations

82
UniTVelo: temporally unified RNA velocity reinforces single-cell trajectory inference DOI Creative Commons
Mingze Gao, Chen Qiao, Yuanhua Huang

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 3, 2022

Abstract The recent breakthrough of single-cell RNA velocity methods brings attractive promises to reveal directed trajectory on cell differentiation, states transition and response perturbations. However, the existing are often found return erroneous results, partly due model violation or lack temporal regularization. Here, we present UniTVelo, a statistical framework that models dynamics spliced unspliced RNAs via flexible transcription activities. Uniquely, it also supports inference unified latent time across transcriptome. With ten datasets, demonstrate UniTVelo returns expected in different biological systems, including hematopoietic differentiation those even with weak kinetics complex branches.

Language: Английский

Citations

73
Mapping human adult hippocampal neurogenesis with single-cell transcriptomics: Reconciling controversy or fueling the debate? DOI Creative Commons
Giorgia Tosoni, Dilara Ayyildiz, Julien Bryois

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(11), P. 1714 - 1731.e3

Published: April 3, 2023

The notion of exploiting the regenerative potential human brain in physiological aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing restoring function. However, major first question address is whether does possess ability regenerate. existence adult hippocampal neurogenesis (AHN) has been at center fierce scientific debate many years. advent single-cell transcriptomic technologies was initially viewed as panacea resolving this controversy. recent RNA sequencing studies hippocampus yielded conflicting results. Here, we critically discuss and re-analyze previously published AHN-related datasets. We argue that, although promising, profiling AHN can be confounded by methodological, conceptual, biological factors that need consistently addressed across openly discussed within community.

Language: Английский

Citations

45
Prediction of single-cell RNA expression profiles in live cells by Raman microscopy with Raman2RNA DOI
Koseki J. Kobayashi-Kirschvink, Charles Comiter,

Shreya Gaddam

et al.

Nature Biotechnology, Journal Year: 2024, Volume and Issue: 42(11), P. 1726 - 1734

Published: Jan. 10, 2024

Language: Английский

Citations

33
The future of rapid and automated single-cell data analysis using reference mapping DOI Creative Commons
Mohammad Lotfollahi, Yuhan Hao, Fabian J. Theis

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(10), P. 2343 - 2358

Published: May 1, 2024

As the number of single-cell datasets continues to grow rapidly, workflows that map new data well-curated reference atlases offer enormous promise for biological community. In this perspective, we discuss key computational challenges and opportunities reference-mapping algorithms. We how mapping algorithms will enable integration diverse across disease states, molecular modalities, genetic perturbations, species eventually replace manual laborious unsupervised clustering pipelines.

Language: Английский

Citations

33
Mapping cells through time and space with moscot DOI Creative Commons
Dominik Klein, Giovanni Palla, Marius Lange

et al.

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

Published: Jan. 22, 2025

Abstract Single-cell genomic technologies enable the multimodal profiling of millions cells across temporal and spatial dimensions. However, experimental limitations hinder comprehensive measurement under native dynamics in their tissue niche. Optimal transport has emerged as a powerful tool to address these constraints facilitated recovery original cellular context 1–4 . Yet, most optimal applications are unable incorporate information or scale single-cell atlases. Here we introduce multi-omics (moscot), scalable framework for genomics that supports multimodality all applications. We demonstrate capability moscot efficiently reconstruct developmental trajectories 1.7 million from mouse embryos 20 time points. To illustrate space, enrich transcriptomic datasets by mapping profiles liver sample align multiple coronal sections brain. present moscot.spatiotemporal, an approach leverages gene-expression data both dimensions uncover spatiotemporal embryogenesis. also resolve endocrine-lineage relationships delta epsilon previously unpublished mouse, time-resolved pancreas development dataset using paired measurements gene expression chromatin accessibility. Our findings confirmed through validation NEUROD2 regulator progenitor model human induced pluripotent stem cell islet differentiation. Moscot is available open-source software, accompanied extensive documentation.

Language: Английский

Citations

9
Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification DOI Creative Commons
Punn Augsornworawat, Nathaniel J. Hogrebe, Matthew Ishahak

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(6), P. 904 - 916

Published: May 15, 2023

Abstract Insulin-producing β cells created from human pluripotent stem have potential as a therapy for insulin-dependent diabetes, but cell-derived islets (SC-islets) still differ their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility transcriptional profiles primary islets. Here provide an analysis that enabled derivation gene lists activity identifying each SC-islet type compared with Within SC-islets, found difference between awry enterochromaffin-like is gradient states rather than stark identity. Furthermore, transplantation improved cellular identities overtime, while long-term vitro culture did not. Collectively, our results highlight importance landscapes during islet maturation.

Language: Английский

Citations

43