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Reduced chromatin accessibility correlates with resistance to Notch activation
Jelle van den Ameele1,2, Robert Krautz1,3, Seth W Cheetham1,4
1The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
Nature Communications
|April 26, 2022
Summary
Notch signaling regulates brain development by controlling neural stem cell (NSC) genes. In progeny cells, reduced chromatin accessibility may limit Notch
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- The Notch signaling pathway is crucial for cell fate decisions during development and in diseases like cancer.
- In the brain, Notch influences neural stem cell (NSC) proliferation, neuronal migration, and maturation.
- Understanding how NOTCH and RBPJ regulate specific gene networks in different brain cell types in vivo is essential.
Purpose of the Study:
- To identify the in vivo binding sites of NOTCH and RBPJ in mouse embryonic cerebral cortex neural stem cells and their progeny.
- To elucidate the gene regulatory networks controlled by NOTCH and RBPJ in these distinct cell types.
Main Methods:
- Utilized Targeted DamID (TaDa) technology, which requires a small number of cells.
- Applied TaDa to mouse embryonic cerebral cortex tissue to map NOTCH and RBPJ binding.
Main Results:
- NOTCH and RBPJ were found to bind to a wide range of genes specific to neural stem cells.
- A decrease in chromatin accessibility was observed in intermediate progenitors and neurons compared to NSCs.
- This decrease in accessibility correlated with the repression of NSC-specific Notch target genes, suggesting a mechanism for restricting NOTCH activity.
Conclusions:
- NOTCH and RBPJ associate with a broad set of NSC genes.
- Chromatin compaction appears to play a role in limiting NOTCH-mediated gene activation as cells differentiate.
- This study provides insights into the dynamic regulation of Notch signaling during brain development.
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