Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell
Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell
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DOI：
10.1182/bloodadvances.2017010413
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发表时间：
2018-04-24
期刊：
影响因子：
7.5
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Ochiai, Kyoko;Kondo, Haruka;Igarashi, Kazuhiko
转录因子（TF）干扰素调节因子-4（IRF 4）通过与包括AP-1-IRF复合元件、Ets-IRF复合元件（EICE）和干扰素序列应答元件（ISRE）的替代DNA基序结合来促进生发中心（GC）反应和浆细胞（PC）分化。尽管所有这些基序都介导IRF 4的转录激活，但仍不清楚一些IRF 4靶基因在PC分化后如何下调。在这里，我们揭示了在PC分化过程中IRF 4介导的基因下调的分子机制。通过结合IRF 4染色质免疫沉淀序列和基因表达分析，我们确定了IRF 4结合区域的锌指-IRF复合元件（ZICE）与PC中表达下调的基因对齐。锌指TF Ikaros和Aiolos被鉴定为PC中的IRF 4结合配偶体，Ikaros而不是Aiolos对于IRF 4与ZICE序列的结合和PC分化是必需的。Ebf 1基因，积极控制B细胞活化和GC反应，被确定为Ikaros/IRF 4靶基因之一。重要的是，虽然ZICE嵌入了ISRE基序，但IRF 4结合ZICE基序作为异二聚体与Ikaros结合，以抑制靶基因，包括Ebf 1。相反，如果锌指基序与EICE基序并置，则Ikaros/PU.1/IRF 4复合物起激活靶基因表达的作用。我们的研究结果揭示了IRF 4在PC分化后的一种新的活性模式，其中在形成Ikaros/IRF 4 DNA结合复合物后，一个基因子集被抑制。
The transcription factor (TF) interferon regulatory factor-4 (IRF4) promotes both germinal center (GC) reactions and plasma cell (PC) differentiation by binding to alternative DNA motifs including AP-1-IRF composite elements, Ets-IRF composite elements (EICEs), and interferon sequence response elements (ISREs). Although all of these motifs mediate transcriptional activation by IRF4, it is still unknown how some of the IRF4 target genes are downregulated upon PC differentiation. Here, we revealed a molecular mechanism of IRF4-mediated gene downregulation during PC differentiation. By combining IRF4 chromatin immunoprecipitation sequence and gene expression analysis, we identified zinc finger-IRF composite elements (ZICEs) in IRF4 binding regions aligned with genes whose expression was downregulated in PCs. The zinc finger TFs Ikaros and Aiolos were identified as IRF4 binding partners in PCs, and Ikaros but not Aiolos was essential for IRF4 binding to the ZICE sequence and for PC differentiation. The Ebf1 gene, which positively controls B-cell activation and GC reactions, was identified as one of the Ikaros/IRF4 target genes. Importantly, while the ZICE embeds the ISRE motif, IRF4 bound the ZICE motif as heterodimers with Ikaros for repression of target genes, which include Ebf1. In contrast, if the zinc finger motif is juxtaposed to the EICE motif, the Ikaros/PU.1/IRF4 complex functioned to activate target gene expression. Our findings revealed a novel mode of IRF4 activity upon PC differentiation where upon forming an Ikaros/IRF4 DNA-bound complex, a subset of genes is repressed.