Arenzana Teresita L, Schjerven Hilde, Smale Stephen T
Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095, USA;
Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
Genes Dev. 2015 Sep 1;29(17):1801-16. doi: 10.1101/gad.266999.115. Epub 2015 Aug 27.
The DNA-binding protein Ikaros is a potent tumor suppressor and hematopoietic regulator. However, the mechanisms by which Ikaros functions remain poorly understood, due in part to its atypical DNA-binding properties and partnership with the poorly understood Mi-2/NuRD complex. In this study, we analyzed five sequential stages of thymocyte development in a mouse strain containing a targeted deletion of Ikaros zinc finger 4, which exhibits a select subset of abnormalities observed in Ikaros-null mice. By examining thymopoiesis in vivo and in vitro, diverse abnormalities were observed at each developmental stage. RNA sequencing revealed that each stage is characterized by the misregulation of a limited number of genes, with a strong preference for stage-specific rather than lineage-specific genes. Strikingly, individual genes rarely exhibited Ikaros dependence at all stages. Instead, a consistent feature of the aberrantly expressed genes was a reduced magnitude of expression level change during developmental transitions. These results, combined with analyses of the interplay between Ikaros loss of function and Notch signaling, suggest that Ikaros may not be a conventional activator or repressor of defined sets of genes. Instead, a primary function may be to sharpen the dynamic range of gene expression changes during developmental transitions via atypical molecular mechanisms that remain undefined.
DNA结合蛋白Ikaros是一种强大的肿瘤抑制因子和造血调节因子。然而，Ikaros发挥功能的机制仍知之甚少，部分原因在于其非典型的DNA结合特性以及与了解较少的Mi-2/NuRD复合物的相互作用。在本研究中，我们分析了一种小鼠品系中胸腺细胞发育的五个连续阶段，该品系的Ikaros锌指4存在靶向缺失，表现出在Ikaros基因敲除小鼠中观察到的一部分异常。通过体内和体外检查胸腺生成，在每个发育阶段都观察到了多种异常。RNA测序显示，每个阶段的特征是有限数量基因的调控异常，强烈偏向于阶段特异性而非谱系特异性基因。引人注目的是，单个基因在所有阶段很少表现出对Ikaros的依赖性。相反，异常表达基因的一个一致特征是在发育转变过程中表达水平变化的幅度减小。这些结果，结合对Ikaros功能丧失与Notch信号之间相互作用的分析，表明Ikaros可能不是特定基因集的传统激活剂或抑制剂。相反，其主要功能可能是通过仍未明确的非典型分子机制，在发育转变过程中增强基因表达变化的动态范围。
