scholarly journals Putative regulators for the continuum of erythroid differentiation revealed by single-cell transcriptome of human BM and UCB cells

2020 ◽  
Vol 117 (23) ◽  
pp. 12868-12876 ◽  
Author(s):  
Peng Huang ◽  
Yongzhong Zhao ◽  
Jianmei Zhong ◽  
Xinhua Zhang ◽  
Qifa Liu ◽  
...  
Keyword(s):  
Single Cell ◽  
Regulatory Networks ◽  
Erythroid Differentiation ◽  
Transcriptional Regulatory Networks ◽  
Hematopoietic Stem ◽  
Delayed Differentiation ◽  
Transcriptional Regulatory ◽  
Cell Transcriptome ◽  
Fine Resolution ◽  
Terminal Erythroid Differentiation

Fine-resolution differentiation trajectories of adult human hematopoietic stem cells (HSCs) involved in the generation of red cells is critical for understanding dynamic developmental changes that accompany human erythropoiesis. Using single-cell RNA sequencing (scRNA-seq) of primary human terminal erythroid cells (CD34−CD235a+) isolated directly from adult bone marrow (BM) and umbilical cord blood (UCB), we documented the transcriptome of terminally differentiated human erythroblasts at unprecedented resolution. The insights enabled us to distinguish polychromatic erythroblasts (PolyEs) at the early and late stages of development as well as the different development stages of orthochromatic erythroblasts (OrthoEs). We further identified a set of putative regulators of terminal erythroid differentiation and functionally validated three of the identified genes,AKAP8L,TERF2IP, andRNF10, by monitoring cell differentiation and apoptosis. We documented that knockdown ofAKAP8Lsuppressed the commitment of HSCs to erythroid lineage and cell proliferation and delayed differentiation of colony-forming unit-erythroid (CFU-E) to the proerythroblast stage (ProE). In contrast, the knockdown ofTERF2IPandRNF10delayed differentiation of PolyE to OrthoE stage. Taken together, the convergence and divergence of the transcriptional continuums at single-cell resolution underscore the transcriptional regulatory networks that underlie human fetal and adult terminal erythroid differentiation.

scholarly journals Single-cell transcriptomics dissects hematopoietic cell destruction and T cell engagement in aplastic anemia

Blood ◽  
2021 ◽  
Author(s):  
Caiying Zhu ◽  
Yu Lian ◽  
Chenchen Wang ◽  
Peng Wu ◽  
Xuan Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aplastic Anemia ◽  
Single Cell ◽  
Regulatory Networks ◽  
Bone Marrow Failure ◽  
Autoimmune Disorder ◽  
Transcriptional Regulatory Networks ◽  
Dna Damage And Repair ◽  
Hematopoietic Stem

Aplastic anemia (AA) is a T cell-mediated autoimmune disorder of the hematopoietic system manifested by severe depletion of the hematopoietic stem and progenitor cells (HSPCs). Nonetheless our understanding of the complex relationship between HSPCs and T cells is still obscure, mainly limited by techniques and the sparsity of HSPCs in the context of bone marrow failure. Here we performed single-cell transcriptome analysis of residual HSPCs and T cells to identify the molecular players from AA patients. We observed that residual HSPCs in AA exhibited lineage-specific alterations in gene expression and transcriptional regulatory networks, indicating a selective disruption of distinct lineage-committed progenitor pools. In particular, HSPCs displayed frequently altered alternative splicing events and skewed patterns of polyadenylation in transcripts related to DNA damage and repair, suggesting a likely role in AA progression to myelodysplastic syndromes. We further identified cell-type-specific ligand-receptor interactions as potential mediators for ongoing HSPCs destruction by T cells. By tracking patients after immunosuppressive therapy (IST), we showed that hematopoiesis remission was incomplete accompanied by IST insensitive interactions between HSPCs and T cells as well as sustained abnormal transcription state. These data collectively constitute the transcriptomic landscape of disrupted hematopoiesis in AA at single-cell resolution, providing new insights into the molecular interactions of engaged T cells with residual HSPCs and render novel therapeutic opportunities for AA.

scholarly journals Identification of KLF6/PSGs and NPY-Related USF2/CEACAM Transcriptional Regulatory Networks via Spinal Cord Bulk and Single-Cell RNA-Seq Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-21
Author(s):  
Xinbing Liu ◽  
Wei Gao ◽  
Wei Liu
Keyword(s):  
Spinal Cord ◽  
Single Cell ◽  
Regulatory Networks ◽  
Single Cell Analysis ◽  
Transcriptional Regulatory Network ◽  
Transcriptional Regulator ◽  
Cell Analysis ◽  
Rna Seq ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory

Background. To further understand the development of the spinal cord, an exploration of the patterns and transcriptional features of spinal cord development in newborn mice at the cellular transcriptome level was carried out. Methods. The mouse single-cell sequencing (scRNA-seq) dataset was downloaded from the GSE108788 dataset. Single-cell RNA-Seq (scRNA-Seq) was conducted on cervical and lumbar spinal V2a interneurons from 2 P0 neonates. Single-cell analysis using the Seurat package was completed, and marker mRNAs were identified for each cluster. Then, pseudotemporal analysis was used to analyze the transcription changes of marker mRNAs in different clusters over time. Finally, the functions of these marker mRNAs were assessed by enrichment analysis and protein-protein interaction (PPI) networks. A transcriptional regulatory network was then constructed using the TRRUST dataset. Results. A total of 949 cells were screened. Single-cell analysis was conducted based on marker mRNAs of each cluster, which revealed the heterogeneity of neonatal mouse spinal cord neuronal cells. Functional analysis of pseudotemporal trajectory-related marker mRNAs suggested that pregnancy-specific glycoproteins (PSGs) and carcinoembryonic antigen cell adhesion molecules (CEACAMs) were the core mRNAs in cluster 3. GSVA analysis then demonstrated that the different clusters had differences in pathway activity. By constructing a transcriptional regulatory network, USF2 was identified to be a transcriptional regulator of CEACAM1 and CEACAM5, while KLF6 was identified to be a transcriptional regulator of PSG3 and PSG5. This conclusion was then validated using the Genotype-Tissue Expression (GTEx) spinal cord transcriptome dataset. Conclusions. This study completed an integrated analysis of a single-cell dataset with the utilization of marker mRNAs. USF2/CEACAM1&5 and KLF6/PSG3&5 transcriptional regulatory networks were identified by spinal cord single-cell analysis.

scholarly journals Single-Cell Transcriptomics-Based Study of Transcriptional Regulatory Features in the Mouse Brain Vasculature

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Wei-Wei Lin ◽  
Lin-Tao Xu ◽  
Yi-Sheng Chen ◽  
Ken Go ◽  
Chenyu Sun ◽  
...  
Keyword(s):  
Single Cell ◽  
Mouse Brain ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Transcriptional Regulatory Network ◽  
Rna Seq ◽  
Brain Vasculature ◽  
Transcriptional Regulatory ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

Background. The critical role of vascular health on brain function has received much attention in recent years. At the single-cell level, studies on the developmental processes of cerebral vascular growth are still relatively few. Techniques for constructing gene regulatory networks (GRNs) based on single-cell transcriptome expression data have made significant progress in recent years. Herein, we constructed a single-cell transcriptional regulatory network of mouse cerebrovascular cells. Methods. The single-cell RNA-seq dataset of mouse brain vessels was downloaded from GEO (GSE98816). This cell clustering was annotated separately using singleR and CellMarker. We then used a modified version of the SCENIC method to construct GRNs. Next, we used a mouse version of SEEK to assess whether genes in the regulon were coexpressed. Finally, regulatory module analysis was performed to complete the cell type relationship quantification. Results. Single-cell RNA-seq data were used to analyze the heterogeneity of mouse cerebrovascular cells, whereby four cell types including endothelial cells, fibroblasts, microglia, and oligodendrocytes were defined. These subpopulations of cells and marker genes together characterize the molecular profile of mouse cerebrovascular cells. Through these signatures, key transcriptional regulators that maintain cell identity were identified. Our findings identified genes like Lmo2, which play an important role in endothelial cells. The same cell type, for instance, fibroblasts, was found to have different regulatory networks, which may influence the functional characteristics of local tissues. Conclusions. In this study, a transcriptional regulatory network based on single-cell analysis was constructed. Additionally, the study identified and profiled mouse cerebrovascular cells using single-cell transcriptome data as well as defined TFs that affect the regulatory network of the mouse brain vasculature.

scholarly journals Effects of poor sleep on the immune cell landscape as assessed by single-cell analysis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Xiuxing Liu ◽  
Binyao Chen ◽  
Zhaohao Huang ◽  
Runping Duan ◽  
He Li ◽  
...  
Keyword(s):  
Single Cell ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Tumor Development ◽  
Public Health Issue ◽  
Poor Sleep ◽  
Transcriptional Regulatory Networks ◽  
Transcriptional Regulatory

AbstractPoor sleep has become an important public health issue. With loss of sleep durations, poor sleep has been linked to the increased risks for diseases. Here we employed mass cytometry and single-cell RNA sequencing to obtain a comprehensive human immune cells landscape in the context of poor sleep, which was analyzed in the context of subset composition, gene signatures, enriched pathways, transcriptional regulatory networks, and intercellular interactions. Participants subjected to staying up had increased T and plasma cell frequency, along with upregulated autoimmune-related markers and pathways in CD4+ T and B cells. Additionally, staying up reduced the differentiation and immune activity of cytotoxic cells, indicative of a predisposition to infection and tumor development. Finally, staying up influenced myeloid subsets distribution and induced inflammation development and cellular senescence. These findings could potentially give high-dimensional and advanced insights for understanding the cellular and molecular mechanisms of pathologic conditions related to poor sleep.

scholarly journals Single-cell transcriptomics reveals a new dynamical function of transcription factors during embryonic hematopoiesis

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Isabelle Bergiers ◽  
Tallulah Andrews ◽  
Özge Vargel Bölükbaşı ◽  
Andreas Buness ◽  
Ewa Janosz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Endothelial Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Cell Transcriptome ◽  
Dynamical Function ◽  
Single Cell Transcriptome

Recent advances in single-cell transcriptomics techniques have opened the door to the study of gene regulatory networks (GRNs) at the single-cell level. Here, we studied the GRNs controlling the emergence of hematopoietic stem and progenitor cells from mouse embryonic endothelium using a combination of single-cell transcriptome assays. We found that a heptad of transcription factors (Runx1, Gata2, Tal1, Fli1, Lyl1, Erg and Lmo2) is specifically co-expressed in an intermediate population expressing both endothelial and hematopoietic markers. Within the heptad, we identified two sets of factors of opposing functions: one (Erg/Fli1) promoting the endothelial cell fate, the other (Runx1/Gata2) promoting the hematopoietic fate. Surprisingly, our data suggest that even though Fli1 initially supports the endothelial cell fate, it acquires a pro-hematopoietic role when co-expressed with Runx1. This work demonstrates the power of single-cell RNA-sequencing for characterizing complex transcription factor dynamics.

scholarly journals Single Cell Pluripotency Regulatory Networks

2016 ◽  
Author(s):  
Patrick S. Stumpf ◽  
Rob Ewing ◽  
Ben D. MacArthur
Keyword(s):  
Single Cell ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Es Cells ◽  
Embryonic Stem ◽  
Transcriptional Regulatory Networks ◽  
Cell Behaviour ◽  
Transcriptional Regulatory ◽  
Spatiotemporal Integration

AbstractEmbryonic stem (ES) cells represent a popular model system for investigating development, tissue regeneration and repair. Although much is known about the molecular mechanisms that regulate the balance between self-renewal and lineage commitment in ES cells, the spatiotemporal integration of responsive signalling pathways with core transcriptional regulatory networks are complex and only partially understood. Moreover, measurements made on populations of cells reveal only average properties of the underlying regulatory networks, obscuring their fine detail. Here, we discuss the reconstruction of regulatory networks in individual cells using novel single cell transcriptomics and proteomics, in order to expand our understanding of the molecular basis of pluripotency, including the role of cell-cell variability within ES cell populations, and ways in which networks may be controlled in order to reliably manipulate cell behaviour.

Transcriptional Control of Parturition: Insights from Gene Regulation Studies in the Myometrium

2021 ◽  
Author(s):  
Nawrah Khader ◽  
Virlana M Shchuka ◽  
Oksana Shynlova ◽  
Jennifer A Mitchell
Keyword(s):  
Transcription Factors ◽  
Regulatory Networks ◽  
Transcriptional Control ◽  
Progesterone Receptors ◽  
Activator Protein 1 ◽  
Transcriptional Regulatory Networks ◽  
Regulatory Pathways ◽  
Transcriptional Regulatory ◽  
Mechanistic Basis ◽  
Labour Onset

Abstract The onset of labour is a culmination of a series of highly coordinated and preparatory physiological events that take place throughout the gestational period. In order to produce the associated contractions needed for fetal delivery, smooth muscle cells in the muscular layer of the uterus (i.e. myometrium) undergo a transition from quiescent to contractile phenotypes. Here, we present the current understanding of the roles transcription factors play in critical labour-associated gene expression changes as part of the molecular mechanistic basis for this transition. Consideration is given to both transcription factors that have been well-studied in a myometrial context, i.e. activator protein 1 (AP-1), progesterone receptors (PRs), estrogen receptors (ERs), and nuclear factor kappa B (NF-κB), as well as additional transcription factors whose gestational event-driving contributions have been demonstrated more recently. These transcription factors may form pregnancy- and labour- associated transcriptional regulatory networks in the myometrium to modulate the timing of labour onset. A more thorough understanding of the transcription factor-mediated, labour-promoting regulatory pathways holds promise for the development of new therapeutic treatments that can be used for the prevention of preterm labour in at-risk women.

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