scholarly journals Single-cell transcriptomics of the mouse gonadal soma reveals the establishment of sexual dimorphism in distinct cell lineages

2018 ◽  
Author(s):  
Isabelle Stévant ◽  
Françoise Kühne ◽  
Andy Greenfield ◽  
Marie-Christine Chaboissier ◽  
Emmanouil T. Dermitzakis ◽  
...  
Keyword(s):  
Time Series ◽  
Sex Determination ◽  
Single Cell ◽  
Cell Fate ◽  
Somatic Cells ◽  
Supporting Cells ◽  
Single Population ◽  
Cell Lineages ◽  
Multipotent Progenitors ◽  
Distinct Cell

SummarySex determination is a unique process that allows the study of multipotent progenitors and their acquisition of sex-specific fates during differentiation of the gonad into a testis or an ovary. Using time-series single-cell RNA sequencing (scRNA-seq) on ovarian Nr5a1-GFP+ somatic cells during sex determination, we identified a single population of early progenitors giving rise to both pre-granulosa cells and potential steroidogenic precursor cells. By comparing time-series scRNA-seq of XX and XY somatic cells, we demonstrate that the supporting cells emerge from the early progenitors with a non-sex-specific transcriptomic program, before pre-granulosa and Sertoli cells acquire their sex-specific identity. In XX and XY steroidogenic precursors similar transcriptomic profiles underlie the acquisition of cell fate, but with a delay in XX cells. Our data provide a novel framework, at single-cell resolution, for further interrogation of the molecular and cellular basis of mammalian sex determination.

scholarly journals FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data

2017 ◽  
Author(s):  
J.S. Herman ◽  
Sagar ◽  
D. Grün
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Learning Algorithm ◽  
Cell Fates ◽  
Lineage Differentiation ◽  
Multipotent Progenitors ◽  
Distinct Cell ◽  
Distinct Lineage ◽  
Cell Transcriptome

Differentiation of multipotent cells is a complex process governed by interactions of thousands of genes subject to substantial expression fluctuations. Resolving cell state heterogeneity arising during this process requires quantification of gene expression within individual cells. However, computational methods linking this heterogeneity to biases towards distinct cell fates are not well established. Here, we perform deep single-cell transcriptome sequencing of ~2,000 bone-marrow derived mouse hematopoietic progenitors enriched for lymphoid lineages. To resolve subtle transcriptome priming indicative of distinct lineage biases, we developed FateID, an iterative supervised learning algorithm for the probabilistic quantification of cell fate bias. FateID delineates domains of fate bias within progenitor populations and permits the derivation of high-resolution differentiation trajectories, revealing a common progenitor population of B cells and plasmacytoid dendritic cells, which we validated by in vitro differentiation assays. We expect that FateID will enhance our understanding of the process of cell fate choice in complex multi-lineage differentiation systems.

scholarly journals Generative modeling of single-cell population time series for inferring cell differentiation landscapes

2020 ◽  
Author(s):  
Grace H.T. Yeo ◽  
Sachit D. Saksena ◽  
David K. Gifford
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Cell Differentiation ◽  
Single Cell ◽  
Cell Fate ◽  
Lineage Tracing ◽  
Model Framework ◽  
Modeling Framework ◽  
Generative Modeling ◽  
Model Complex

SummaryExisting computational methods that use single-cell RNA-sequencing for cell fate prediction either summarize observations of cell states and their couplings without modeling the underlying differentiation process, or are limited in their capacity to model complex differentiation landscapes. Thus, contemporary methods cannot predict how cells evolve stochastically and in physical time from an arbitrary starting expression state, nor can they model the cell fate consequences of gene expression perturbations. We introduce PRESCIENT (Potential eneRgy undErlying Single Cell gradIENTs), a generative modeling framework that learns an underlying differentiation landscape from single-cell time-series gene expression data. Our generative model framework provides insight into the process of differentiation and can simulate differentiation trajectories for arbitrary gene expression progenitor states. We validate our method on a recently published experimental lineage tracing dataset that provides observed trajectories. We show that this model is able to predict the fate biases of progenitor cells in neutrophil/macrophage lineages when accounting for cell proliferation, improving upon the best-performing existing method. We also show how a model can predict trajectories for cells not found in the model’s training set, including cells in which genes or sets of genes have been perturbed. PRESCIENT is able to accommodate complex perturbations of multiple genes, at different time points and from different starting cell populations. PRESCIENT models are able to recover the expected effects of known modulators of cell fate in hematopoiesis and pancreatic β cell differentiation.

scholarly journals Single cell transcriptomics reveal temporal dynamics of critical regulators of germ cell fate during mouse sex determination

2019 ◽  
Author(s):  
Chloé Mayère ◽  
Yasmine Neirijnck ◽  
Pauline Sararols ◽  
Chris M Rands ◽  
Isabelle Stévant ◽  
...  
Keyword(s):  
Sex Determination ◽  
Germ Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Gene Networks ◽  
Network Inference ◽  
Temporal Dynamics ◽  
Intron Retention ◽  
Gonad Development ◽  
Altered Expression

SummaryDespite the importance of germ cell (GC) differentiation for sexual reproduction, the gene networks underlying their fate remain unclear. Here, we comprehensively characterize the gene expression dynamics during sex determination based on single-cell RNA sequencing of 14,914 XX and XY mouse GCs between embryonic days (E) 9.0 and 16.5. We found that XX and XY GCs diverge transcriptionally as early as E11.5 with upregulation of genes downstream of the Bone morphogenic protein (BMP) and Nodal/Activin pathways in XY and XX GCs, respectively. We also identified a sex-specific upregulation of genes associated with negative regulation of mRNA processing and an increase in intron retention consistent with a reduction in mRNA splicing in XY testicular GCs by E13.5. Using computational gene regulation network inference analysis, we identified sex-specific, sequential waves of putative key regulator genes during GC differentiation and revealed that the meiotic genes are regulated by positive and negative master modules acting in an antagonistic fashion. Finally, we found that rare adrenal GCs enter meiosis similarly to ovarian GCs but display altered expression of master genes controlling the female and male genetic programs, indicating that the somatic environment is important for GC function. Our data is available on a web platform and provides a molecular roadmap of GC sex determination at single-cell resolution, which will serve as a valuable resource for future studies of gonad development, function and disease.

Cell movements and cell fate during zebrafish gastrulation

Development ◽  
1992 ◽  
Vol 116 (Supplement) ◽  
pp. 65-73 ◽  
Author(s):  
Robert K. Ho
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Fate Map ◽  
Cell Fates ◽  
Cell Lineages ◽  
Cell Position ◽  
Vertebrate Embryo ◽  
Cellular Identity ◽  
Transplantation Experiments

The early lineages of the zebrafish are indeterminate and a single cell labeled before the late blastula period will contribute progeny to a variety of tissues. Therefore, early cell lineages in the zebrafish do not establish future cell fates and early blastomeres must necessarily remain pluripotent. Eventually, after a period of random cell mixing, individual cells do become tissue restricted according to their later position within the blastoderm. The elucidation of a fate map for the zebrafish gastrula (Kimmel et al., 1990), has made it possible to study the processes by which cellular identity is conferred and maintained in the zebrafish. In this chapter, I describe single cell transplantation experiments designed to test for the irreversible restriction or ‘commitment’ of embryonic blastomeres in the zebrafish embryo. These experiments support the hypothesis that cell fate in the vertebrate embryo is determined by cell position. Work on the spadetail mutation will also be reviewed; this mutation causes a subset of mesodermal precursors to mismigrate during gastrulation thereby leading to a change in their eventual cell identity.

scholarly journals The single-cell epigenetic regulatory landscape in mammalian perinatal testis development

2021 ◽  
Author(s):  
Jinyue Liao ◽  
Hoi Ching Suen ◽  
Shitao Rao ◽  
Alfred Chun Shui Luk ◽  
Ruoyu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Cell Type

AbstractSpermatogenesis depends on an orchestrated series of developing events in germ cells and full maturation of the somatic microenvironment. To date, the majority of efforts to study cellular heterogeneity in testis has been focused on single-cell gene expression rather than the chromatin landscape shaping gene expression. To advance our understanding of the regulatory programs underlying testicular cell types, we analyzed single-cell chromatin accessibility profiles in more than 25,000 cells from mouse developing testis. We showed that scATAC-Seq allowed us to deconvolve distinct cell populations and identify cis-regulatory elements (CREs) underlying cell type specification. We identified sets of transcription factors associated with cell type-specific accessibility, revealing novel regulators of cell fate specification and maintenance. Pseudotime reconstruction revealed detailed regulatory dynamics coordinating the sequential developmental progressions of germ cells and somatic cells. This high-resolution data also revealed putative stem cells within the Sertoli and Leydig cell populations. Further, we defined candidate target cell types and genes of several GWAS signals, including those associated with testosterone levels and coronary artery disease. Collectively, our data provide a blueprint of the ‘regulon’ of the mouse male germline and supporting somatic cells.

scholarly journals FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data

2018 ◽  
Vol 15 (5) ◽  
pp. 379-386 ◽  
Author(s):  
Josip S Herman ◽  
Sagar ◽  
Dominic Grün
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Rna Seq ◽  
Multipotent Progenitors

scholarly journals Single‐cell transcriptomics reveal temporal dynamics of critical regulators of germ cell fate during mouse sex determination

2021 ◽  
Vol 35 (4) ◽  
Author(s):  
Chloé Mayère ◽  
Yasmine Neirijnck ◽  
Pauline Sararols ◽  
Chris M. Rands ◽  
Isabelle Stévant ◽  
...  
Keyword(s):  
Sex Determination ◽  
Germ Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Temporal Dynamics

scholarly journals The Chromatin State during Gonadal Sex Determination

2021 ◽  
pp. 1-9
Author(s):  
Shannon Dupont ◽  
Blanche Capel
Keyword(s):  
Sex Determination ◽  
Cell Fate ◽  
Granulosa Cell ◽  
Histone Modifications ◽  
Granulosa Cells ◽  
Gonad Development ◽  
Chromatin State ◽  
Supporting Cells ◽  
Direct Role ◽  
Specific Factors

At embryonic day (E) 10.5, prior to gonadal sex determination, XX and XY gonads are bipotential and able to differentiate into either a testis or an ovary. At this point, they are transcriptionally and morphologically indistinguishable. Sex determination begins around E11.5 in the mouse when the supporting cell lineage commits to either Sertoli or granulosa cell fate. Testis-specific factors such as SRY and SOX9 drive differentiation of bipotential-supporting cells into the Sertoli cell pathway, whereas ovary-specific factors like WNT4 and FOXL2 guide differentiation into granulosa cells. It is known that these 2 pathways are mutually antagonistic, and repression of the alternative fate is critical for maintenance of the testis or ovary programs. While we understand much about the transcription factor networks guiding the process of sex determination, it is only more recently that we have begun to understand how this process is epigenetically controlled. Studies in the past decade have demonstrated the importance of the chromatin state for gene expression and cell fate commitment, with histone modifications and DNA accessibility having a direct role in gene regulation. It is now clear that the chromatin state during sex determination is dynamic and likely critical for the establishment and/or maintenance of the transcriptional programs. Prior to sex determination, supporting cells have similar chromatin structure and histone modification profiles, reflecting the bipotential nature of these cells. After differentiation to Sertoli or granulosa cells, the chromatin state acquires sex-specific profiles. The proteins that regulate the deposition of histone modifications or the opening of compact chromatin likely play an important role in Sertoli and granulosa cell fate commitment and gonad development. Here, we describe studies profiling the chromatin state during gonadal sex determination and one example in which depletion of <i>Cbx2</i>, a member of the Polycomb Repressive Complex 1 (PRC1), causes male-to-female sex reversal due to a failure to repress the ovarian pathway.

scholarly journals Hidden heterogeneity and circadian-controlled cell fate inferred from single cell lineages

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Shaon Chakrabarti ◽  
Andrew L. Paek ◽  
Jose Reyes ◽  
Kathleen A. Lasick ◽  
Galit Lahav ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Cell Lineages

scholarly journals Single-cell transcriptomics identifies divergent developmental lineage trajectories during human pituitary development

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shu Zhang ◽  
Yueli Cui ◽  
Xinyi Ma ◽  
Jun Yong ◽  
Liying Yan ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Developmental Trajectories ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Human Pituitary ◽  
Pituitary Development ◽  
Physiological Processes ◽  
Distinct Cell ◽  
Transcriptional Landscape

Abstract The anterior pituitary gland plays a central role in regulating various physiological processes, including body growth, reproduction, metabolism and stress response. Here, we perform single-cell RNA-sequencing (scRNA-seq) of 4113 individual cells from human fetal pituitaries. We characterize divergent developmental trajectories with distinct transitional intermediate states in five hormone-producing cell lineages. Corticotropes exhibit an early intermediate state prior to full differentiation. Three cell types of the PIT-1 lineage (somatotropes, lactotropes and thyrotropes) segregate from a common progenitor coexpressing lineage-specific transcription factors of different sublineages. Gonadotropes experience two multistep developmental trajectories. Furthermore, we identify a fetal gonadotrope cell subtype expressing the primate-specific hormone chorionic gonadotropin. We also characterize the cellular heterogeneity of pituitary stem cells and identify a hybrid epithelial/mesenchymal state and an early-to-late state transition. Here, our results provide insights into the transcriptional landscape of human pituitary development, defining distinct cell substates and subtypes and illustrating transcription factor dynamics during cell fate commitment.

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