Inaccessible LCG Promoters Act as Safeguards to Restrict T Cell Development to Appropriate Notch Signaling Environments.
Inaccessible LCG Promoters Act as Safeguards to Restrict T Cell Development to Appropriate Notch Signaling Environments.
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DOI：
10.1016/j.stemcr.2021.02.017
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发表时间：
2021-04-13
影响因子：
5.9
通讯作者：
Bernstein ID
中科院分区：
文献类型：
--
作者：
Furuyama S;Wu QV;Varnum-Finney B;Sandstrom R;Meuleman W;Stamatoyannopoulos JA;Bernstein ID
T细胞的发育仅限于胸腺，并依赖于胸腺微环境中诱导的高水平的Notch信号。为了了解Notch在胸腺限制中的功能，我们研究了Notch信号强度的定量差异对靶基因选择性的基础，重点是T细胞分化所必需基因的染色质结构。我们发现，需要高的Notch信号强度来激活对T细胞承诺至关重要的已知靶点的启动子，包括Il2ra、CD3DNA和Rag1，这些靶点具有低CpG含量(Lcg)和ε在造血干细胞中不可及的特点。我们的发现表明，启动子DNA在LCG T谱系基因上的不可访问性提供了强大的保护，防止在不适当的Notch信号背景下随机激活，限制T细胞发育到胸腺。Notch靶基因启动子对Notch信号强度的不同反应T细胞承诺靶具有低CpG含量和DNA不可及的特点HSPC启动子DNA不可及性保护T细胞靶基因免受随机激活LCG启动子作为Notch诱导分化的保护措施Bernstein及其同事研究了靶基因选择性对Notch信号强度的定量差异的响应。他们的发现表明，基本T细胞承诺靶点启动子上的低CpG含量和DNA不可及性提供了强大的保护，防止在不适当的Notch信号背景下随机激活基因，确保T细胞的发育仅限于富含Notch配体的胸腺。
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. 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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Lun AT;Smyth GK
通讯作者：
Smyth GK
影响因子：
4.3
作者：
Eden E;Lipson D;Yogev S;Yakhini Z
通讯作者：
Yakhini Z
影响因子：
16.6
作者：
Gama-Norton L;Ferrando E;Ruiz-Herguido C;Liu Z;Guiu J;Islam AB;Lee SU;Yan M;Guidos CJ;López-Bigas N;Maeda T;Espinosa L;Kopan R;Bigas A
通讯作者：
Bigas A
影响因子：
64.5
作者：
MCBLANE, JF;VANGENT, DC;OETTINGER, MA
通讯作者：
OETTINGER, MA