The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

2019 ◽  
Author(s):  
Gabriel Aughey
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Chromatin Accessibility ◽  
Cell Cycle Exit

scholarly journals The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

2018 ◽  
Author(s):  
Yiqin Ma ◽  
Daniel J McKay ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Chromatin Accessibility ◽  
Cell Cycle Gene ◽  
Cell Cycle Regulators ◽  
Cell Cycle Exit ◽  
Cell Cycle Genes ◽  
Repressor Complex ◽  
Pupal Wing ◽  
A Cell

During terminal differentiation most cells will exit the cell cycle and enter into a prolonged or permanent G0. Cell cycle exit is usually initiated through the repression of cell cycle gene expression by formation of a transcriptional repressor complex called DREAM. However when DREAM repressive function is compromised during terminal differentiation, additional unknown mechanisms act to stably repress cycling and ensure robust cell cycle exit. Here we provide evidence that developmentally programmed, temporal changes in chromatin accessibility at a subset of critical cell cycle genes acts to enforce cell cycle exit during terminal differentiation in the Drosophila melanogaster wing. We show that during terminal differentiation, chromatin closes at a set of pupal wing enhancers for the key rate-limiting cell cycle regulators cycE, e2f1 and stg. This closing coincides with wing cells entering a robust postmitotic state that is strongly refractory to cell cycle re-activation. When cell cycle exit is genetically disrupted, chromatin accessibility at cell cycle genes remains largely unaffected and the closing of enhancers at cycE, e2f1 and stg proceeds independent of the cell cycling status. Instead, disruption of cell cycle exit leads to changes in accessibility and expression of a subset of hormone-induced transcription factors involved in the progression of terminal differentiation. Our results uncover a mechanism that acts as a cell cycle-independent timer to limit aberrant cycling in terminally differentiating tissues. In addition, we provide a new molecular description of the cross-talk between cell cycle exit and terminal differentiation during metamorphosis.

scholarly journals Chromatin organization changes during the establishment and maintenance of the postmitotic state

2017 ◽  
Author(s):  
Yiqin Ma ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Gene Silencing ◽  
Ectopic Expression ◽  
Terminal Differentiation ◽  
Chromatin Organization ◽  
Cell Cycle Exit ◽  
Heterochromatin Protein 1 ◽  
Developmental Potential ◽  
Close Relationship ◽  
The Face

SummaryBackgroundGenome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle and existing data suggests a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit.ResultsWe focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G0 in this tissue, a flexible G0 period where cells can be induced to re-enter the cell cycle under specific genetic manipulations and a state we call “robust”, where cells become strongly refractory to cell cycle re-entry. Compromising the flexible G0 by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin-associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1(HP1). However, this disruption is reversible. When cells enter a robust G0 state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin associated modifications are restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities.ConclusionsHeterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit.

scholarly journals A Double-Assurance Mechanism Controls Cell Cycle Exit upon Terminal Differentiation in Drosophila

2007 ◽  
Vol 12 (4) ◽  
pp. 631-643 ◽  
Author(s):  
Laura A. Buttitta ◽  
Alexia J. Katzaroff ◽  
Carissa L. Perez ◽  
Aida de la Cruz ◽  
Bruce A. Edgar
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Cell Cycle Exit

scholarly journals Tropomodulin3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver

Blood ◽  
2014 ◽  
Vol 123 (5) ◽  
pp. 758-767 ◽  
Author(s):  
Zhenhua Sui ◽  
Roberta B. Nowak ◽  
Andrea Bacconi ◽  
Nancy E. Kim ◽  
Hui Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Fetal Liver ◽  
Terminal Differentiation ◽  
Cell Types ◽  
Cell Cycle Exit ◽  
Erythroid Progenitors ◽  
Island Formation ◽  
Erythroid Terminal Differentiation ◽  
Embryonic Lethal ◽  
Key Points

Key Points Tmod3 deletion leads to reduced erythroid progenitors and impaired erythroblast survival, cell-cycle exit, and enucleation. Erythroblast-macrophage islands are reduced in the absence of Tmod3, which is required in both cell types for island formation.

scholarly journals BAF subunit switching regulates chromatin accessibility to control cell cycle exit in the developing mammalian cortex

2021 ◽  
Vol 35 (5-6) ◽  
pp. 335-353 ◽  
Author(s):  
Simon M.G. Braun ◽  
Ralitsa Petrova ◽  
Jiong Tang ◽  
Andrey Krokhotin ◽  
Erik L. Miller ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Control Cell ◽  
Chromatin Accessibility ◽  
Cell Cycle Exit

CUL-4A Targets p27 for Degradation and Regulates Proliferation, Cell Cycle Exit, and Differentiation during Erythropoiesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1358-1358
Author(s):  
Kristin T. Chun ◽  
Nan Jia ◽  
Yahaira M. Naaldjik ◽  
Reuben Kapur ◽  
Binghui Li
Keyword(s):  
Cell Cycle ◽  
Ubiquitin Ligase ◽  
Tritiated Thymidine ◽  
Terminal Differentiation ◽  
Beta Globin ◽  
Cell Cycle Exit ◽  
Erythroid Progenitors ◽  
Erythroid Terminal Differentiation ◽  
Over Expression ◽  
Lineage Specific Genes

Abstract As erythroid progenitors differentiate into precursors and finally mature red blood cells, they induce the expression of lineage-specific genes, and their proliferation declines until cell cycle exit. CUL-4A encodes a core subunit of a ubiquitin ligase that targets proteins for ubiquitin-mediated degradation, and CUL-4A haploinsufficient mice display hematopoietic dysregulation with fewer multipotential and erythroid committed progenitors (3-fold and 5-fold, respectively). In this study, stress induced by 5-fluorouracil or phenylhydrazine reveals a delay in the ability of CUL-4A +/− mice to recover erythroid progenitors and precursors and to reestablish normal hematocrits. Conversely, over-expression of CUL-4A in a growth factor-dependent, proerythroblast cell line increases proliferation 34% (tritiated thymidine incorporation) and the proportion of cells in S-phase 5%. When these cells are induced to terminally differentiate, endogenous CUL-4A protein expression declines 3.6-fold. Its enforced expression interferes with erythrocyte maturation (beta-globin induction) and cell cycle exit, and instead promotes proliferation. Furthermore, p27 accumulates during erythroid terminal differentiation, but CUL-4A enforced expression increases p27 protein turnover nearly 7-fold and attenuates its accumulation. CUL-4A and p27 proteins co-immunoprecipitate, indicating that a Cul-4A ubiquitin ligase targets p27 for degradation. These findings suggest that a Cul-4A ubiquitin ligase positively regulates proliferation by targeting p27 for degradation and that CUL-4A down-regulation during erythroid terminal differentiation allows p27 to accumulate and signal cell cycle exit.

scholarly journals A G1 Checkpoint Mediated by the Retinoblastoma Protein That Is Dispensable in Terminal Differentiation but Essential for Senescence

2009 ◽  
Vol 30 (4) ◽  
pp. 948-960 ◽  
Author(s):  
Srikanth Talluri ◽  
Christian E. Isaac ◽  
Mohammad Ahmad ◽  
Shauna A. Henley ◽  
Sarah M. Francis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Terminal Differentiation ◽  
Retinoblastoma Protein ◽  
Genotoxic Stress ◽  
Cell Types ◽  
Cell Cycle Exit ◽  
Chromatin Regulators ◽  
Permanent Cell ◽  
And Function

ABSTRACT Terminally differentiated cell types are needed to live and function in a postmitotic state for a lifetime. Cellular senescence is another type of permanent arrest that blocks the proliferation of cells in response to genotoxic stress. Here we show that the retinoblastoma protein (pRB) uses a mechanism to block DNA replication in senescence that is distinct from its role in permanent cell cycle exit associated with terminal differentiation. Our work demonstrates that a subtle mutation in pRB that cripples its ability to interact with chromatin regulators impairs heterochromatinization and repression of E2F-responsive promoters during senescence. In contrast, terminally differentiated nerve and muscle cells bearing the same mutation fully exit the cell cycle and block E2F-responsive gene expression by a different mechanism. Remarkably, this reveals that pRB recruits chromatin regulators primarily to engage a stress-responsive G1 arrest program.

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