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Changes in chromatin accessibility ensure robust cell cycle exit in terminally differentiated cells
- Source :
- PLoS Biology, PLoS Biology, Vol 17, Iss 9, p e3000378 (2019)
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- During terminal differentiation, most cells exit the cell cycle and enter into a prolonged or permanent G0 in which they are refractory to mitogenic signals. Entry into G0 is usually initiated through the repression of cell cycle gene expression by formation of a transcriptional repressor complex called dimerization partner (DP), retinoblastoma (RB)-like, E2F and MuvB (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 small subset of critical cell cycle genes act 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 Cyclin E (cycE), E2F transcription factor 1 (e2f1), and string (stg). This closing coincides with wing cells entering a robust postmitotic state that is strongly refractory to cell cycle reactivation, and the regions that close contain known binding sites for effectors of mitogenic signaling pathways such as Yorkie and Notch. When cell cycle exit is genetically disrupted, chromatin accessibility at cell cycle genes remains unaffected, and the closing of distal 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 the response to mitogenic signaling and 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.<br />The longer a cell remains in G0, the more refractory it becomes to re-entering the cell cycle. This study shows that in terminally differentiated cells in vivo, regulatory elements at genes encoding just three key cell cycle regulators (cycE, e2f1 and stg) become inaccessible, limiting their aberrant activation and maintaining a prolonged, robust G0.
- Subjects :
- 0301 basic medicine
Cellular differentiation
Gene Expression
Biochemistry
Mechanical Treatment of Specimens
0302 clinical medicine
Wings, Animal
E2F1
Regulatory Elements, Transcriptional
Cell Cycle and Cell Division
Biology (General)
Cell Disruption
Chromosome Biology
General Neuroscience
Cell Cycle
Metamorphosis, Biological
Gene Expression Regulation, Developmental
Cell Differentiation
Cell cycle
Cell Cycle Gene
Chromatin
Cell biology
Drosophila melanogaster
Specimen Disruption
Cell Processes
Epigenetics
General Agricultural and Biological Sciences
Research Article
QH301-705.5
Biology
Research and Analysis Methods
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Transcriptional repressor complex
DNA-binding proteins
Genetics
Animals
Gene Regulation
E2F
Transcription factor
Metamorphosis
General Immunology and Microbiology
Biology and Life Sciences
Proteins
Cell Biology
Regulatory Proteins
030104 developmental biology
Specimen Preparation and Treatment
030217 neurology & neurosurgery
Developmental Biology
Transcription Factors
Subjects
Details
- ISSN :
- 15457885
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- PLOS Biology
- Accession number :
- edsair.doi.dedup.....0dea3fee91ae4d61f1276047f8fd253e