scholarly journals Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Humberto Contreras-Trujillo ◽  
Jiya Eerdeng ◽  
Samir Akre ◽  
Du Jiang ◽  
Jorge Contreras ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Dna Barcode ◽  
Treatment Resistance ◽  
Experimental System ◽  
Transcriptome Profiling ◽  
Intratumoral Heterogeneity ◽  
Cellular Heterogeneity ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

AbstractCellular heterogeneity is a major cause of treatment resistance in cancer. Despite recent advances in single-cell genomic and transcriptomic sequencing, it remains difficult to relate measured molecular profiles to the cellular activities underlying cancer. Here, we present an integrated experimental system that connects single cell gene expression to heterogeneous cancer cell growth, metastasis, and treatment response. Our system integrates single cell transcriptome profiling with DNA barcode based clonal tracking in patient-derived xenograft models. We show that leukemia cells exhibiting unique gene expression respond to different chemotherapies in distinct but consistent manners across multiple mice. In addition, we uncover a form of leukemia expansion that is spatially confined to the bone marrow of single anatomical sites and driven by cells with distinct gene expression. Our integrated experimental system can interrogate the molecular and cellular basis of the intratumoral heterogeneity underlying disease progression and treatment resistance.

scholarly journals Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses

2021 ◽  
Author(s):  
Rong Lu ◽  
HUMBERTO CONTRERAS-TRUJILLO ◽  
JIYA EERDENG ◽  
SAMIR AKRE ◽  
DU JIANG ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Dna Barcode ◽  
Treatment Resistance ◽  
Intratumoral Heterogeneity ◽  
Integrated System ◽  
Cellular Heterogeneity ◽  
Gene Expression Signatures ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Abstract Cellular heterogeneity is a major cause of treatment resistance in cancer. Despite recent advances in single-cell genomic and transcriptomic sequencing, it remains difficult to relate measured molecular profiles to the cellular activities underlying cancer. Here, we present an integrated experimental system that connects single cell gene expression to heterogeneous cancer cell growth, metastasis, and treatment response. Our system integrates single cell transcriptome profiling with DNA barcode based clonal tracking in patient-derived xenograft models. We show that leukemia cells exhibiting unique gene expression signatures respond to different chemotherapies in distinct but consistent manners across multiple mice. In addition, we uncover an unexpected yet common form of leukemia expansion that is spatially confined to the bone marrow of single anatomical sites and driven by cells with distinct gene expression signatures. Our integrated system directly and effectively interrogates the molecular and cellular basis of the intratumoral heterogeneity underlying disease progression and treatment resistance.

scholarly journals Combinatorial action of transcription factors in open chromatin contributes to early cellular heterogeneity and organizer mesendoderm specification

2020 ◽  
Author(s):  
Ann Rose Bright ◽  
Siebe van Genesen ◽  
Qingqing Li ◽  
Simon J. van Heeringen ◽  
Alexia Grasso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Single Cell ◽  
Marginal Zone ◽  
Chromatin Accessibility ◽  
Cellular Heterogeneity ◽  
Open Chromatin ◽  
Cell Clusters ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

ABSTRACTDuring gastrulation, mesoderm is induced in pluripotent cells, concomitant with dorsal-ventral patterning and establishing of the dorsal axis. How transcription factors operate within the constraints of chromatin accessibility to mediate these processes is not well-understood. We applied chromatin accessibility and single cell transcriptome analyses to explore the emergence of heterogeneity and underlying gene-regulatory mechanisms during early gastrulation in Xenopus. ATAC-sequencing of pluripotent animal cap cells revealed a state of open chromatin of transcriptionally inactive lineage-restricted genes, whereas chromatin accessibility in dorsal marginal zone cells more closely reflected the transcriptional activity of genes. We characterized single cell trajectories in animal cap and dorsal marginal zone in early gastrula embryos, and inferred the activity of transcription factors in single cell clusters by integrating chromatin accessibility and single cell RNA-sequencing. We tested the activity of organizer-expressed transcription factors in mesoderm-competent animal cap cells and found combinatorial effects of these factors on organizer gene expression. In particular the combination of Foxb1 and Eomes induced a gene expression profile that mimicked those observed in head and trunk organizer single cell clusters. In addition, genes induced by Eomes, Otx2 or the Irx3-Otx2 combination, were enriched for promoters with maternally regulated H3K4me3 modifications, whereas promoters selectively induced by Lhx8 were marked more frequently by zygotically controlled H3K4me3. Our results show that combinatorial activity of zygotically expressed transcription factors acts on maternally-regulated accessible chromatin to induce organizer gene expression.

scholarly journals Single cell transcriptome profiling of the human developing spinal cord reveals a conserved genetic programme with human specific features

2021 ◽  
Author(s):  
Teresa Rayon ◽  
Rory J. Maizels ◽  
Christopher Barrington ◽  
James Briscoe
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Single Cell ◽  
Motor Neurons ◽  
Neural Tube ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Human Embryos ◽  
Neuronal Populations ◽  
Cell Transcriptome

AbstractThe spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly and physiologically distinct neuronal subtypes that are generated in a characteristic spatial-temporal arrangement from progenitors in the embryonic neural tube. The systematic mapping of gene expression in mouse embryos has provided insight into the diversity and complexity of cells in the neural tube. For human embryos, however, less information has been available. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie Stages (CS) CS12, CS14, CS17 and CS19 from Gestational Weeks (W) 4-7. In total we recovered the transcriptomes of 71,219 cells. Analysis of progenitor and neuronal populations from the neural tube, as well as cells of the peripheral nervous system, in dorsal root ganglia adjacent to the neural tube, identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with existing mouse datasets revealed the overall similarity of mouse and human neural tube development while highlighting specific features that differed between species. These data provide a catalogue of gene expression and cell type identity in the developing neural tube that will support future studies of sensory and motor control systems and can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.

scholarly journals High-Throughput Single-Cell Transcriptome Profiling of Plant Cell Types

Cell Reports ◽  
2019 ◽  
Vol 27 (7) ◽  
pp. 2241-2247.e4 ◽  
Author(s):  
Christine N. Shulse ◽  
Benjamin J. Cole ◽  
Doina Ciobanu ◽  
Junyan Lin ◽  
Yuko Yoshinaga ◽  
...  
Keyword(s):  
Single Cell ◽  
Plant Cell ◽  
High Throughput ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

scholarly journals Single cell transcriptome profiling of developing chick retinal cells

2017 ◽  
Vol 525 (12) ◽  
pp. 2735-2781 ◽  
Author(s):  
Lauren A. Laboissonniere ◽  
Gregory M. Martin ◽  
Jillian J. Goetz ◽  
Ran Bi ◽  
Brock Pope ◽  
...  
Keyword(s):  
Single Cell ◽  
Transcriptome Profiling ◽  
Retinal Cells ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome
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