Sox2 gene regulation via the D1 enhancer in embryonic neural tube and neural crest by the combined action of SOX2 and ZIC2
Sox2 gene regulation via the D1 enhancer in embryonic neural tube and neural crest by the combined action of SOX2 and ZIC2
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DOI：
10.1111/gtc.12753
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发表时间：
2020-02-26
期刊：
影响因子：
2.1
通讯作者：
Kondoh, Hisato
中科院分区：
文献类型：
--
作者：
Iida, Hideaki;Furukawa, Yoko;Kondoh, Hisato
转录因子（TF）SOX 2通过与共结合增强子序列的细胞类型特异性伴侣TF的功能相互作用来调节各种干细胞和组织祖细胞。神经祖细胞是主要的胚胎组织，其中SOX 2承担中心调节作用。为了表征SOX2在神经祖细胞中的伴侣TF，我们使用鸡胚电穿孔研究了在胚胎神经管（NT）和神经嵴（NC）中激活的Sox 2基因的D1增强子的调节。我们确定了SOX和两个ZIC TF在D1增强子激活中的重要TF结合位点。通过比较D1增强子激活的背腹和前后模式，以及突变对增强子激活模式与TF表达模式的影响，我们确定SOX 2和ZIC 2为主要的D1增强子激活TF。通过染色质免疫沉淀分析证实了这些TF与D1增强子序列的结合。SOX 2和ZIC 2 TF的组合激活了NT和NC中的增强子。这些结果表明，SOX 2和ZIC 2，这已被称为发挥主要的调节作用，在神经祖细胞，功能合作。此外，最近证实的SOX 2表达在NC发展过程中占至少部分由D1增强子活性。然而，从小鼠基因组中删除D1增强子序列并不影响小鼠的发育，这表明其他增强子的功能冗余。
The transcription factor (TF) SOX2 regulates various stem cells and tissue progenitors via functional interactions with cell type-specific partner TFs that co-bind to enhancer sequences. Neural progenitors are the major embryonic tissues where SOX2 assumes central regulatory roles. In order to characterize the partner TFs of SOX2 in neural progenitors, we investigated the regulation of the D1 enhancer of the Sox2 gene, which is activated in the embryonic neural tube (NT) and neural crest (NC), using chicken embryo electroporation. We identified essential TF binding sites for a SOX, and two ZIC TFs in the activation of the D1 enhancer. By comparison of dorso-ventral and antero-posterior patterns of D1 enhancer activation, and the effect of mutations on the enhancer activation patterns with TF expression patterns, we determined SOX2 and ZIC2 as the major D1 enhancer-activating TFs. Binding of these TFs to the D1 enhancer sequence was confirmed by chromatin immunoprecipitation analysis. The combination of SOX2 and ZIC2 TFs activated the enhancer in both the NT and NC. These results indicate that SOX2 and ZIC2, which have been known to play major regulatory roles in neural progenitors, do functionally cooperate. In addition, the recently demonstrated SOX2 expression during the NC development is accounted for at least partly by the D1 enhancer activity. Deletion of the D1 enhancer sequence from the mouse genome, however, did not affect the mouse development, indicating functional redundancies of other enhancers.