Inaccessible LCG Promoters Act as Safeguards to Restrict T Cell Development to Appropriate Notch Signaling Environments
| Autor: | Irwin D. Bernstein, Wouter Meuleman, Suzanne Furuyama, Richard Sandstrom, Qian 'Vicky' Wu, Barbara Varnum-Finney, John A. Stamatoyannopoulos |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Notch T cell T-Lymphocytes DNA accessibility Notch signaling pathway Biology Biochemistry Recombination-activating gene Article 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Deoxyribonuclease I Progenitor cell Promoter Regions Genetic Receptors Notch T cell development Promoter Cell Biology DNA Cell biology Chromatin Mice Inbred C57BL Haematopoiesis 030104 developmental biology medicine.anatomical_structure CpG site LCG promoters CpG Islands 030217 neurology & neurosurgery Developmental Biology Signal Transduction |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary T cell development is restricted to the thymus and is dependent on high levels of Notch signaling induced within the thymic microenvironment. To understand Notch function in thymic restriction, we investigated the basis for target gene selectivity in response to quantitative differences in Notch signal strength, focusing on the chromatin architecture of genes essential for T cell differentiation. We find that high Notch signal strength is required to activate promoters of known targets essential for T cell commitment, including Il2ra, Cd3ε, and Rag1, which feature low CpG content (LCG) and DNA inaccessibility in hematopoietic stem progenitor cells. Our findings suggest that promoter DNA inaccessibility at LCG T lineage genes provides robust protection against stochastic activation in inappropriate Notch signaling contexts, limiting T cell development to the thymus. Highlights • Notch target gene promoters differentially respond to Notch signal strength • T cell commitment targets feature low CpG content and DNA inaccessibility in HSPCs • Promoter DNA inaccessibility protects T cell target genes from stochastic activation • LCG promoters act as safeguards of Notch-induced differentiation Bernstein and colleagues investigate target gene selectivity in response to quantitative differences in Notch signal strength. Their findings suggest that low CpG content and DNA inaccessibility at the promoters of essential T cell commitment targets provide robust protection against stochastic gene activation in inappropriate Notch signaling contexts, ensuring that T cell development is limited to the Notch ligand-rich thymus. |
| Databáze: | OpenAIRE |
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