Global increase in replication fork speed during a p57 KIP2 -regulated erythroid cell fate switch

Chen

et al. 2018

Preprint

Cell proliferation changes concomitantly with fate transitions during reprogramming, differentiation, regeneration, and oncogenesis. Methods to resolve cell cycle length heterogeneity in real-time are currently lacking. Here, we describe a genetically encoded fluorescent reporter that captures live cell cycle speed using a single measurement. This reporter is based on the color-changing Fluorescent Timer (FT) protein, which emits blue fluorescence when newly synthesized before maturing into a red fluorescent protein. We generated a mouse strain expressing an H2B-FT fusion reporter from a universally active locus, and demonstrate that faster-cycling cells can be distinguished from slowercycling ones based on the intracellular fluorescence ratio between the FT's blue and red states. Using this reporter, we reveal the native cell cycle speed distributions of fresh hematopoietic cells, and demonstrate its utility in analyzing cell proliferation in solid tissues. This system is broadly applicable for dissecting functional heterogeneity associated with cell cycle dynamics in complex tissues.

Section: Discussionsupporting

confidence: 79%

Section: H2b-ft Blue/red Ratio Provides An Estimate Of Cell Cycle Lensupporting

confidence: 85%

Resolving cell cycle speed in one snapshot with a live-cell fluorescent reporter

Chen

et al. 2018

Preprint

“…This cell cycle‐facilitated fate transition is echoed by differentiating tissue stem cells in vivo , where differentiation is often accompanied by a period of rapid proliferation . How cell cycle dynamics impart specific cell fate choices during lineage specification continues to be an active area of research . Cells of the hematopoietic system, for example, display extensive heterogeneity in cell cycle dynamics .…”

Section: Cell Cycle Speed Varies In Many Cellular Contextsmentioning

confidence: 99%

“…The rapid progression of S‐phase is dependent on the downregulation of the CDK inhibitor p57 KIP2 . Low p57 KIP2 leads to global increase in replication fork speed, activation of the erythroid master transcriptional regulator GATA‐1, as well as formation of DNase I hypersensitive sites and DNA demethylation of these loci . It remains to be determined whether S‐phase acceleration is the cause or consequence of the transcriptional changes driving terminal erythroid commitment and how replication fork speed integrates with these processes.…”

Section: Specific Cell Cycle Phases Integrating With Cell Fate Determmentioning

confidence: 99%

“…For example, M‐phase is widely considered invariable in length , although an exception to this rule is found in the developing mouse neocortex, where prolonged mitosis in radial glia is associated with divergent fate commitment . Similarly, S‐phase length is generally constrained but its shortening is seen in erythroid differentiation and neural progenitor commitment . Below, we will first discuss how overall cell cycle speed may impact cell fate decisions without discriminating the specific mode of cell cycle length modulation.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cell cycle dynamics in the reprogramming of cellular identity

Guo

2019

FEBS Letters

Reprogramming of cellular identity is fundamentally at odds with replication of the genome: cell fate reprogramming requires complex multidimensional epigenomic changes, whereas genome replication demands fidelity. In this review, we discuss how the pace of the genome's replication and cell cycle influences the way daughter cells take on their identity. We highlight several biochemical processes that are pertinent to cell fate control, whose propagation into the daughter cells should be governed by more complex mechanisms than simple templated replication. With this mindset, we summarize multiple scenarios where rapid cell cycle could interfere with cell fate copying and promote cell fate reprogramming. Prominent examples of cell fate regulation by specific cell cycle phases are also discussed. Overall, there is much to be learned regarding the relationship between cell fate reprogramming and cell cycle control. Harnessing cell cycle dynamics could greatly facilitate the derivation of desired cell types.

The palette of techniques for cell cycle analysis

Guo

2020

FEBS Letters

The cell division cycle is the generational period of cellular growth and propagation. Cell cycle progression needs to be highly regulated to preserve genomic fidelity while increasing cell number. In multicellular organisms, the cell cycle must also coordinate with cell fate specification during development and tissue homeostasis. Altered cell cycle dynamics play a central role also in a number of pathophysiological processes. Thus, extensive effort has been made to define the biochemical machineries that execute the cell cycle and their regulation, as well as implementing more sensitive and accurate cell cycle measurements. Here, we review the available techniques for cell cycle analysis, revisiting the assumptions behind conventional population-based measurements and discussing new tools to better address cell cycle heterogeneity in the single-cell era. We weigh the strengths, weaknesses, and trade-offs of methods designed to measure temporal aspects of the cell cycle. Finally, we discuss emerging techniques for capturing cell cycle speed at single-cell resolution in live animals.