Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity
Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity
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DOI：
10.1038/s41375-019-0474-0
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发表时间：
2019-11-01
期刊：
影响因子：
11.4
通讯作者：
Dovat, Sinisa
中科院分区：
文献类型：
--
作者：
Ding, Yali;Zhang, Bo;Dovat, Sinisa
Ikaros编码一种转录因子，在T细胞急性淋巴细胞白血病（T-ALL）中作为肿瘤抑制因子发挥作用。Ikaros调节T-ALL中基因表达和细胞增殖的机制尚不清楚。将Ikaros重新引入Ikaros无效的T-ALL细胞中导致细胞增殖停止和T细胞分化诱导。我们进行了动态，全球，表观基因组和基因表达分析，以确定Ikaros肿瘤抑制活性的机制。我们的研究结果确定了新的Ikaros在基因表达的表观遗传调控中的功能：Ikaros直接调节从头形成和增强子的耗尽，从头形成活性增强子和激活平衡增强子; Ikaros直接诱导超级增强子的形成; Ikaros通过直接调节染色质可及性表现出开创性的活性。动态分析表明Ikaros DNA结合对增强子激活、增强子和超级增强子的从头形成以及染色质可及性的长期影响。我们的研究结果表明，Ikaros的肿瘤抑制功能是通过增强子和超级增强子景观的全局调节以及通过开拓性活动发生的。表达分析鉴定了大量由Ikaros和Ikaros诱导的增强子直接调节的新型信号传导途径，并且这些信号传导途径负责T-ALL细胞中增殖的停止和T细胞分化的诱导。
Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Reintroduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros' tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.