The Tumor Suppressor Ikaros Shapes the Repertoire of Notch Target Genes in T Cells
The Tumor Suppressor Ikaros Shapes the Repertoire of Notch Target Genes in T Cells
复制标题
DOI：
10.1126/scisignal.2004545
复制
发表时间：
2014-03-18
影响因子：
7.3
通讯作者：
Chan, Susan
中科院分区：
文献类型：
--
作者：
Geimer Le Lay, Anne-Solen;Oravecz, Attila;Chan, Susan
Notch信号通路在许多细胞类型中被激活，但其作用是细胞类型和阶段特异性的。在免疫系统中，Notch活性是T细胞祖细胞分化所必需的，但在更成熟的胸腺细胞中，Notch活性降低，其中Notch是致癌的。基于单基因模型的研究表明，肿瘤抑制蛋白Ikaros在抑制Notch靶基因的转录中起重要作用。我们使用全基因组分析，包括染色质免疫沉淀测序，以确定由Notch和Ikaros控制的基因在获得和丧失功能的实验。我们发现Ikaros与Notch激活的大多数基因结合并直接抑制其表达。胸腺细胞中Ikaros的特异性缺失导致Notch靶基因的持续表达，该靶基因对于T细胞成熟以及小鼠中T细胞白血病的快速发展至关重要。Notch靶基因的表达通常在T细胞中沉默，但在其他细胞类型中被Notch激活，发生在Ikaros遗传缺陷小鼠的T细胞中。我们建议Ikaros通过广泛靶向Notch调控序列附近的元件来塑造T细胞中Notch转录反应的时间和库。这些结果为理解组织特异性和肿瘤相关Notch反应的调控提供了分子框架。
The Notch signaling pathway is activated in many cell types, but its effects are cell type- and stage specific. In the immune system, Notch activity is required for the differentiation of T cell progenitors, but it is reduced in more mature thymocytes, in which Notch is oncogenic. Studies based on single gene models have suggested that the tumor suppressor protein Ikaros plays an important role in repressing the transcription of Notch target genes. We used genome-wide analyses, including chromatin immunoprecipitation sequencing, to identify genes controlled by Notch and Ikaros in gain- and loss-of-function experiments. We found that Ikaros bound to and directly repressed the expression of most genes that are activated by Notch. Specific deletion of Ikaros in thymocytes led to the persistent expression of Notch target genes that are essential for T cell maturation, as well as the rapid development of T cell leukemias in mice. Expression of Notch target genes that are normally silent in T cells, but are activated by Notch in other cell types, occurred in T cells of mice genetically deficient in Ikaros. We propose that Ikaros shapes the timing and repertoire of the Notch transcriptional response in T cells through widespread targeting of elements adjacent to Notch regulatory sequences. These results provide a molecular framework for understanding the regulation of tissue-specific and tumor-related Notch responses.