Single-cell analysis of mixed-lineage states leading to a binary cell fate choice

Olsson, André; Venkatasubramanian, Meenakshi; Chaudhri, Virendra K.; Aronow, Bruce J.; Salomonis, Nathan; Singh, Harinder; Grimes, H. Leighton

doi:10.1038/nature19348

Cited by 461 publications

(351 citation statements)

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“…“GMPs” were originally defined as LKS − CD34 + FcγR hi cells (Akashi et al, 2000). However, in addition to progenitors with dual granulocyte-monocyte potential (oligopotent or multi-lineage GMPs), this fraction contains granulocyte-committed progenitors (GPs) and monocyte-committed progenitors (MPs or cMoPs) (Akashi et al, 2000; Hettinger et al, 2013; Olsson et al, 2016; Yanez et al, 2015), which we recently reported can be separated on the basis of their expression of Ly6C and CD115 (GMPs are Ly6C − CD115 lo , GPs are Ly6C + CD115 lo , and MPs are Ly6C + CD115 hi (Yanez et al, 2015)). As expected, viSNE analysis confirmed the presence of subsets corresponding to GMPs, GPs and MPs/cMoPs in the LKS − CD34 + FcγR hi fraction of mouse bone marrow (Figure S1A–B).…”

Section: Resultsmentioning

confidence: 99%

“…However, recent studies have challenged hierarchical models of hematopoiesis and instead suggested that progenitors make lineage commitment decisions at an earlier stage than previously thought (Notta et al, 2016; Paul et al, 2015). A hybrid of these two scenarios is also possible, with some early progenitors losing multipotency and immediately adopting a particular fate, and others undergoing progressive lineage restriction under the control of competing transcriptional programs (Drissen et al, 2016; Olsson et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

et al. 2017

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Summary Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar, but distinct, monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6Chi) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of “neutrophil-like” monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

et al. 2017

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“…Several recent reports have demonstrated the potential of single cell RNA-seq to provide new resolution of TF network architecture (Kolodziejczyk et al, 2015, Olsson et al, 2016, Scialdone et al, 2016). It is of course important to remember the experimental caveats.…”

Section: Recent Insights From Emerging Technologiesmentioning

confidence: 99%

“…First, mRNA levels do not always correspond to TF protein level (or activity). Second, single cell RNA-seq alone cannot distinguish indirect vs. direct TF interactions, although here, its combination with genetic deletion of specific TFs has yielded important resolution (Olsson et al, 2016, Scialdone et al, 2016). Third, current single cell RNA-seq approaches generally have lower sequencing coverage than bulk cell analyses, which may influence the transcript detection and/or observed intercellular heterogeneity.…”

Section: Recent Insights From Emerging Technologiesmentioning

confidence: 99%

Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity

2017

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Transcription factor (TF) networks are a key determinant of cell fate decisions in mammalian development and adult tissue homeostasis, and are frequently corrupted in disease. However, our inability to experimentally resolve and interrogate the complexity of mammalian TF networks has hampered the progress in this field. Recent technological advances, in particular large-scale genome-wide approaches, single-cell methodologies, live-cell imaging, and genome editing, are emerging as important technologies in TF network biology. Several recent studies even suggest a need to re-evaluate established models of mammalian TF networks. Here, we provide a brief overview of current and emerging methods to define mammalian TF networks. We also discuss how these emerging technologies facilitate new ways to interrogate complex TF networks, consider the current open questions in the field, and comment on potential future directions and biomedical applications.

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“…43,56 Genome-wide analysis reveals that certain groups of genes are associated with distinct development stages and subsets of DCs. Dendritic cell commitment (e.g., MPP → CDP transition) is associated with down-regulation of genes (e.g., CCAAT/enhancer-binding protein alpha, GATA2, GFI1, and T-cell acute lymphocytic leukemia protein 1) that restrict hematopoietic cell differentiation from HSPCs 49,75,86 and up-regulation of CDP signature genes (e.g., E2F2 and HOXA1) associated with cell cycle. 56 Interestingly, pan-DC genes (e.g., FLT3, IRF5, SPIB, and STAT1), which are expressed in both cDCs and pDCs but expressed at low levels in MPP and CDP, are known to regulate the overall generation and immune response of DCs.…”

Section: Epigenetic Organization Of Hierarchical Tf Network In DC Prmentioning

confidence: 99%

Epigenetic Regulation of Dendritic Cell Development and Function

Tian¹,

Meng²,

Zhang³

2017

Cancer J

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The immune system is characterized by the generation of structurally and functionally heterogeneous immune cells that constitute complex innate and adaptive immunity. This heterogeneity of immune cells results from changes in the expression of genes without altering DNA sequence. To achieve this heterogeneity, immune cells orchestrate the expression and functional status of transcription factor (TF) networks, which can be broadly categorized into 3 classes: pioneer TFs that facilitate initial commitment and differentiation of hematopoietic cells, subset-specific TFs that promote the generation of selected cell lineages, and immune-signaling TFs that regulate specialized function in differentiated cells. Epigenetic mechanisms are known to be critical for organizing the TF networks, thereby controlling immune cell lineage-fate decisions, plasticity, and function. The effects of epigenetic regulators can be heritable during cell mitosis, primarily through the modification of DNA and histone methylation patterns at gene loci. By doing so, the immune system is enabled to mount a selective but robust response to stimuli, such as pathogens, tumor cells, autoantigens, or allogeneic antigens in the setting of transplantation, while preserving the immune cell reservoir necessary for protecting the host against numerous other unexpected stimuli and limit detrimental effect of systemic inflammatory reactions.

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Single-cell analysis of mixed-lineage states leading to a binary cell fate choice

Cited by 461 publications

References 50 publications

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes

Mammalian Transcription Factor Networks: Recent Advances in Interrogating Biological Complexity

Epigenetic Regulation of Dendritic Cell Development and Function

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