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首页> 外文期刊>Molecular and Cellular Biology >Mutational Analysis of the Poly(ADP-Ribosyl)ation Sites of the Transcription Factor CTCF Provides an Insight into the Mechanism of Its Regulation by Poly(ADP-Ribosyl)ation
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Mutational Analysis of the Poly(ADP-Ribosyl)ation Sites of the Transcription Factor CTCF Provides an Insight into the Mechanism of Its Regulation by Poly(ADP-Ribosyl)ation

机译：转录因子CTCF的聚（ADP-核糖基）化位点的突变分析提供了对其通过聚（ADP-核糖基）化调控的机制的了解。

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Poly(ADP-ribosyl)ation of the conserved multifunctional transcription factor CTCF was previously identified as important to maintain CTCF insulator and chromatin barrier functions. However, the molecular mechanism of this regulation and also the necessity of this modification for other CTCF functions remain unknown. In this study, we identified potential sites of poly(ADP-ribosyl)ation within the N-terminal domain of CTCF and generated a mutant deficient in poly(ADP-ribosyl)ation. Using this CTCF mutant, we demonstrated the requirement of poly(ADP-ribosyl)ation for optimal CTCF function in transcriptional activation of the p19ARF promoter and inhibition of cell proliferation. By using a newly generated isogenic insulator reporter cell line, the CTCF insulator function at the mouse Igf2-H19 imprinting control region (ICR) was found to be compromised by the CTCF mutation. The association and simultaneous presence of PARP-1 and CTCF at the ICR, confirmed by single and serial chromatin immunoprecipitation assays, were found to be independent of CTCF poly(ADP-ribosyl)ation. These results suggest a model of CTCF regulation by poly(ADP-ribosyl)ation whereby CTCF and PARP-1 form functional complexes at sites along the DNA, producing a dynamic reversible modification of CTCF. By using bioinformatics tools, numerous sites of CTCF and PARP-1 colocalization were demonstrated, suggesting that such regulation of CTCF may take place at the genome level.
机译：保守的多功能转录因子CTCF的聚（ADP-核糖基）化以前被认为对维持CTCF绝缘子和染色质屏障功能很重要。但是，这种调节的分子机制以及对其他CTCF功能进行这种修饰的必要性仍然未知。在这项研究中，我们确定了CTCF N末端域内的聚（ADP-核糖基）化的潜在位点，并产生了一个缺乏聚（ADP-核糖基）化的突变体。使用此CTCF突变体，我们证明了聚（ADP-核糖基）化对p 19ARF 启动子的转录激活和细胞增殖抑制的最佳CTCF功能的要求。通过使用新生成的等基因绝缘子报告基因细胞系，发现老鼠的 Igf2-H19 印迹控制区（ICR）的CTCF绝缘子功能受到CTCF突变的损害。通过单次和连续染色质免疫沉淀测定法证实，在ICR处PARP-1和CTCF的缔合和同时存在独立于CTCF聚（ADP-核糖基）。这些结果表明了通过聚（ADP-核糖基）化作用调节CTCF的模型，其中CTCF和PARP-1在沿着DNA的位点形成功能性复合物，产生了动态可逆的CTCF修饰。通过使用生物信息学工具，证明了CTCF和PARP-1共定位的许多位点，表明CTCF的这种调节可能发生在基因组水平上。

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