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首页> 外文期刊>Molecular and Cellular Biology >Differential Recruitment of Methylated CpG Binding Domains by the Orphan Receptor GCNF Initiates the Repression and Silencing of Oct4 Expression
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Differential Recruitment of Methylated CpG Binding Domains by the Orphan Receptor GCNF Initiates the Repression and Silencing of Oct4 Expression

机译：甲基化的CpG绑定域的孤儿受体GCNF的差异招募开始抑制和沉默Oct4表达。

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The pluripotent factor Oct4 is a key transcription factor that maintains embryonic stem (ES) cell self-renewal and is down-regulated upon the differentiation of ES cells and silenced in somatic cells. A combination of cis elements, transcription factors, and epigenetic modifications, such as DNA methylation, are involved in the regulation of Oct4 gene expression. Here we show that the orphan nuclear receptor GCNF initiates Oct4 repression and DNA methylation by the differential recruitment of MBD (methylated CpG binding domain) factors to the promoter. Compared with wild-type ES cells and gastrulating embryos, Oct4 repression is lost and its proximal promoter is significantly hypomethylated in RA-differentiated GCNF?/? ES cells. The Oct4 gene is reexpressed in some somatic cells of GCNF?/? embryos, showing that it has not been properly silenced coincident with reduced DNA methylation of its promoter. Efforts to characterize mediators of GCNF's repressive function and DNA methylation of the Oct4 promoter identified methyl-DNA binding proteins, MBD3 and MBD2, as GCNF-interacting factors. In P19 and ES cells, upon differentiation, endogenous GCNF binds to the Oct4 proximal promoter and differentially recruits MBD3 and MBD2. In differentiated GCNF?/? ES cells, recruitment of MBD3 and MBD2 to the Oct4 promoter is lost, and repression of Oct4 expression and DNA methylation fails to occur. RNA interference-mediated knockdown of MBD3 and/or MBD2 expression results in reduced Oct4 repression in differentiated P19 and ES cells. Repression of Oct4 expression and recruitment of MBD3 are maintained in de novo DNA methylation-deficient ES cells (Dnmt3A/3B-null cells), while MBD2 recruitment is lost. Thus, recruitment of MBD3 and MBD2 by GCNF links two events, gene-specific repression and DNA methylation, which occur differentially at the Oct4 promoter. GCNF initiates the repression and epigenetic modification of Oct4 gene during ES cell differentiation.
机译：多能因子Oct4是维持胚胎干（ES）细胞自我更新并在ES细胞分化后被下调并在体细胞中沉默的关键转录因子。 cis 元素，转录因子和表观遗传修饰（例如DNA甲基化）的组合参与了Oct4基因表达的调节。在这里，我们显示孤儿核受体GCNF通过MBD（ m 乙基化CpG b inding d omain）的差异募集来启动Oct4抑制和DNA甲基化。 ）因素对启动子的影响。与野生型ES细胞和胃胚化胚胎相比，在RA分化的GCNF ？/？ ES细胞中，Oct4阻遏作用消失，其近端启动子明显甲基化。 Oct4基因在某些GCNF ？/？胚胎的体细胞中重新表达，表明与启动子DNA甲基化程度降低同时，Oct4基因没有被适当沉默。表征GCNF阻遏功能和Oct4启动子的DNA甲基化的介质的努力确定了甲基DNA结合蛋白MBD3和MBD2是GCNF的相互作用因子。在P19和ES细胞中，分化后，内源性GCNF结合到Oct4近端启动子，并差异募集MBD3和MBD2。在分化的GCNF ？/？ ES细胞中，MBD3和MBD2向Oct4启动子的募集丢失，并且无法发生Oct4表达的抑制和DNA甲基化。 RNA干扰介导的MBD3和/或MBD2表达的敲低导致分化的P19和ES细胞中Oct4阻遏降低。在从头DNA甲基化缺陷的ES细胞（Dnmt3A / 3B-null细胞）中维持了Oct4表达的抑制和MBD3的募集，而MBD2募集丢失。因此，GCNF对MBD3和MBD2的募集将两个事件联系在一起，即基因特异性抑制和DNA甲基化，这两个事件在Oct4启动子上发生差异。 GCNF启动ES细胞分化过程中Oct4基因的抑制和表观遗传修饰。

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