Inaccessible LCG Promoters Act as Safeguards to Restrict T Cell Development to Appropriate Notch Signaling Environments | Zendy

Suzanne Furuyama | Zendy; Qian Wu | Zendy; Barbara VarnumFinney | Zendy; Richard Sandstrom | Zendy; Wouter Meuleman | Zendy; J Stamatoyannopoulos | Zendy; Irwin D. Bernstein | Zendy

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Inaccessible LCG Promoters Act as Safeguards to Restrict T Cell Development to Appropriate Notch Signaling Environments

Author(s) -

Suzanne Furuyama,

Qian Wu,

Barbara VarnumFinney,

Richard Sandstrom,

Wouter Meuleman,

J Stamatoyannopoulos,

Irwin D. Bernstein

Publication year - 2021

Publication title -

stem cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 3.207

H-Index - 76

ISSN - 2213-6711

DOI - 10.1016/j.stemcr.2021.02.017

Subject(s) - biology , notch signaling pathway , microbiology and biotechnology , chromatin , promoter , progenitor cell , gene , stem cell , signal transduction , cellular differentiation , cell fate determination , haematopoiesis , transcription factor , genetics , gene expression

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.

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