Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Stem Cell Reports. 2021 Apr 13;16(4):717-726. doi: 10.1016/j.stemcr.2021.02.017. Epub 2021 Mar 25.
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.
T 细胞的发育受到限制，仅发生在胸腺中，并且依赖于胸腺微环境中诱导的高水平 Notch 信号。为了理解 Notch 在胸腺限制中的功能，我们研究了针对 Notch 信号强度的定量差异的靶基因选择性的基础，重点是对分化为 T 细胞至关重要的基因的染色质结构。我们发现，高 Notch 信号强度对于激活已知靶基因的启动子是必需的，这些靶基因对于 T 细胞的分化是必需的，包括 Il2ra、Cd3ε 和 Rag1，它们具有造血干细胞祖细胞中低 CpG 含量（LCG）和 DNA 不可及性。我们的发现表明，LCG T 系基因启动子的 DNA 不可及性提供了对不适当 Notch 信号环境中随机激活的强大保护，从而将 T 细胞的发育限制在胸腺中。
