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The shifting shape and functional specializations of the cell cycle during lineage development

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Abstract Essentially all cell cycling in multicellular organisms in vivo takes place in the context of lineage differentiation. This notwithstanding, the regulation of the cell cycle is often assumed to be generic, independent of tissue or developmental stage. Here we review developmental‐stage‐specific cell cycle adaptations that may influence developmental decisions, in mammalian erythropoiesis and in other lineages. The length of the cell cycle influences the balance between self‐renewal and differentiation in multiple tissues, and may determine lineage fate. Shorter cycles contribute to the efficiency of reprogramming somatic cells into induced pluripotency stem cells and help maintain the pluripotent state. While the plasticity of G1 length is well established, the speed of S phase is emerging as a novel regulated parameter that may influence cell fate transitions in the erythroid lineage, in neural tissue and in embryonic stem cells. A slow S phase may stabilize the self‐renewal state, whereas S phase shortening may favor a cell fate change. In the erythroid lineage, functional approaches and single‐cell RNA‐sequencing show that a key transcriptional switch, at the transition from self‐renewal to differentiation, is synchronized with and dependent on S phase. This specific S phase is shorter, as a result of a genome‐wide increase in the speed of replication forks. Furthermore, there is progressive shortening in G1 in the period preceding this switch. Together these studies suggest an integrated regulatory landscape of the cycle and differentiation programs, where cell cycle adaptations are controlled by, and in turn feed back on, the propagation of developmental trajectories. This article is categorized under: Biological Mechanisms > Cell Fates Developmental Biology > Stem Cell Biology and Regeneration Developmental Biology > Lineages
Single‐cell RNA‐sequencing (scRNA‐seq) reveals the early erythroid trajectory. (a) SPRING plot (Weinreb, Wolock, & Klein, 2018) of early (Kit+) hematopoietic bone marrow progenitors. Each dot represents a cell transcriptome. Transcriptomes were arranged, based on their similarity, in a k‐nearest neighbor graph in multidimensional gene expression space, and were then projected onto two dimensions. The graph is a snapshot of a dynamic process in which cells originate at the multi‐potential progenitor state (MPP) and then progress towards one of seven potential branches as they differentiate. The color heatmap represents the probability, for each cell, of attaining one of the seven cell fates, calculated based on the population balance analysis (PBA) algorithm (Weinreb, Wolock, Tusi, Socolovsky, & Klein, 2018) (Reprinted with permission from Tusi et al. (2018) Copyright 2018 Springer Nature). (b) Top: color heatmap for expression of Cd34, Gata1 and Hba‐a1 (alpha globin) in the bone marrow progenitor SPRING plots. Bottom: erythroid trajectory progenitors (corresponding to the branch colored red in “A”) were ordered along a linear axis, starting with MPPs and traversing the entire erythroid branch (cells whose erythroid fate probability increased with increasing distance from MPP were included in the trajectory). The dynamic profiles of Cd34, Gata1 and Hba‐a1 along the linear axis are shown (expression units for Cd34 and Gata1 are on marked on the left y axis, and for Hba‐a1 on the right y axis) (Reprinted with permission from Tusi et al. (2018). Copyright 2018 Springer Nature)
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An S phase dependent erythroid commitment switch. (a) Fetal liver erythroid progenitors and precursors can be identified using flow‐cytometric markers (left panel) and cytospin preparations (right panel). Early progenitors, mostly CFU‐e, are in subset S0. During the transition from S0 to S1, defined by the upregulation of CD71, CFU‐e undergo commitment to enter erythroid terminal differentiation (ETD). Precursors in S2‐S5 are in ETD (Reprinted with permission from Pop et al. (2010). Copyright 2010 Public Library of Science). (b) A cartoon illustrating the synchrony of S phase with the CFU‐e/ETD transition, which takes place at the S0/S1 junction. CFU‐e cells undergoing this transition (purple) are in S phase of the cycle. The transition is dependent on S phase progression and is associated with a transient shortening of both S phase and the total cell cycle length. It also coincides with changes in chromatin configuration at erythroid gene loci
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Dynamic changes in the cell cycle are associated with cell fate decisions. Summary of recurring patterns of cell cycle dynamic change with cell fate transitions (see Table 1 and text). The lengths of both G1 and S phase are regulated by, and potentially contribute to, the execution of key cell fate decisions, including maintenance (short G1) or attainment (short S phase) of pluripotency, and the transition from progenitor self‐renewal to overt cellular differentiation (S phase shortening, G1 lengthening). Both known and suggested mechanisms linking the cycle to cell fate transitions are indicated
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Orchestrated cell cycle remodeling throughout the erythroid trajectory. (a) Progression through the erythroid trajectory is marked by a gradual ramping‐up of cell cycle genes, peaking at the CFU‐e/ETD switch. Examples shown are cyclin A, cyclin E, E2F4, and genes encoding components of the origin replication complex and the MCM helicase. (b) Cell cycle status analysis of erythroid progenitors in vivo shows that an increasing fraction is in S phase, and conversely, fewer are in G1, as cells progress along the trajectory (upper panel). These changes cannot be accounted for by changes in S phase speed (lower panel), suggesting they are the result of progressive shortening in G1. (c) Summary of cell cycle changes that take place during the erythroid trajectory: progressive G1 shortening during the CFU‐e stage, culminating in S phase shortening at the CFU‐e/ETD switch. (Reprinted with permission from Tusi et al. (2018). Copyright 2018 Springer Nature)
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CFU‐e self‐renewal requires a slow S phase, while the switch to ETD coincides with increased replication fork speed and S phase shortening. (a) Replication fork speeds in CFU‐e (= S0, see Figure 1) and ETD (= S1), in wild‐type and p57KIP2‐deficient fetal livers. The CFU‐e to ETD transition involves a 50% increase in fork speeds. CFU‐e fork speeds are slow, as a result of p57KIP2‐mediated CDK inhibition (Reprinted with permission from Hwang et al. (2017). Copyright 2017 American Association for the Advancement of Science (United States)). (b) p57KIP2‐deficient CFU‐e have a fast S phase and fail to undergo self‐renewal in vitro. The addition to the culture medium of a CDK2 inhibiting drug, roscovitine, which slows S phase speed, rescues their self‐renewal (Reprinted with permission from Hwang et al. (2017). Copyright 2017 American Association for the Advancement of Science (United States)). (c) Summary of the S phase speed requirements during self‐renewal and at the transition to ETD
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The erythroid trajectory and the CFU‐e/ETD switch through the lens of scRNA‐seq. (a) The erythroid trajectory includes all cell transcriptomes whose erythroid fate probability (shown as a color heatmap) increases with increasing distance from the MPPs (multipotential progenitors). The erythroid trajectory is subdivided into five contiguous stages: MPPs, EBMPs (erythroid, basophil/mast cell and megakaryocytic progenitors), the classically defined colony forming BFU‐e and CFU‐e progenitors, and precursors undergoing ETD (Reprinted with permission from Tusi et al. (2018). Copyright 2018 Springer Nature). (b) Top panel: the CFU‐e/ETD transition is a sharp transcriptional switch. Genes that are differentially expressed along the erythroid trajectory were ordered by their peak expression. CFU‐e and ETD‐specific genes are marked, as is the sharp CFU‐e/ETD transcriptional switch. Lower panels: the timing of the CFU‐e/ETD switch is not predicted by TF expression. Panels show the dynamic profiles of TFs, cell‐surface markers, and cell cycle‐phase‐specific gene expression. The dynamic profiles of TFs and cell‐surface markers do not explain the timing of the CFU‐e/ETD switch. By contrast, cell cycle phase traces suggest that the CFU‐e/ETD switch is synchronized with S phase of a specific cell cycle. The cell cycle phase traces represent aggregate expression of cell‐cycle phase‐ specific genes. They are largely flat between MPP and the CFU‐e/ETD switch, suggesting that cells are cycling asynchronously. However, at the switch, they form a series of peaks, starting with G1/S and S, corresponding to a specific cell cycle that is synchronized with the CFU‐e/ETD transition (Reprinted with permission from Tusi et al. (2018). Copyright 2018 Springer Nature)
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