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

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: Congenital Diseases > Stem Cells and Development

The role of specialized cell cycles during erythroid lineage development: insights from single-cell RNA sequencing

“…Taken together, both transcriptional and functional approaches suggest remarkable remodeling of the cell cycle that takes place in lock step with developmental events of the erythroid trajectory [16,19,20,23,32]. We observe cells undergoing gradual shortening in G1 as they progress through the BFU-e and CFU-e stages; this is followed by an abrupt shortening in S phase at the CFU-e/ETD switch.…”

“…What is the relevance of these findings to non-erythroid lineages? Although some aspects of cell cycle regulation had been known to be relevant to development for some time, the relevance of S phase duration is becoming clearer only recently [32]. S phase shortening at the onset of mammalian gastrulation had been known for many decades [36,[43][44][45], but was perhaps considered unique to this critical developmental milestone.…”

Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis

“…Unexpectedly, DNA damage checkpoint kinases (ATM, ATR, and CHEK2) were also enriched. During terminal maturation, erythroblasts undergo a series of specialized cell divisions associated with shortened G1 phase and increased lineage-specific gene expression (Hwang, Hidalgo et al, 2020). It is possible that DNA damage checkpoint activity is triggered to control replicative stressinduced damage during this process, similar to what occurs upon ▸ A Heat map of z-scored and differentially regulated kinase and phosphatase abundances (log2 DIA intensities) across differentiation.…”

Skimmianine as a novel therapeutic agent suppresses proliferation and migration of human esophageal squamous cell carcinoma via blocking the activation of ERK1/2

“…Different phases of cell cycle (G1, S, G2 and M) are closely related to key regulatory molecules of cell cycle. Since the length of cell cycle is mainly determined by the length of G1 phase, the most important regulatory targets exist in G1 phase [34,35]. Our study showed that ESCC cells with SK treatment could be stagnated in the G0/G1 phase instead of entering the S phase for DNA replication via inhibiting the expression of 10 Cyclin D1 and CDK4.…”