Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7
Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7
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DOI：
10.1016/j.chembiol.2019.07.013
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发表时间：
2019-10-17
影响因子：
8.6
通讯作者：
Frye, Stephen V.
中科院分区：
文献类型：
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作者：
Lamb, Kelsey N.;Bsteh, Daniel;Frye, Stephen V.
在人类疾病中，多梳定向的基因表达抑制经常被错误调节。利用定量和靶特异性细胞测定来发现第一种有效的正变构调节剂（PAM）肽模拟物UNC4976，其通过CBX 7（Polycomb阻遏复合物1的染色体结构域甲基赖氨酸阅读器）结合核酸。UNC4976的PAM活性通过同时拮抗CBX7向靶基因的H3K27me3特异性募集，同时增加与DNA和RNA的非特异性结合，在三种正交细胞试验中增强了疗效。PAM活性从而使PRC 1重新平衡远离H3K27me3靶区域。总之，我们对UNC4976的发现和表征不仅揭示了迄今为止最有效的PRC1特异性化学探针，而且还揭示了Polycomb调控的潜在机制，并对非组蛋白赖氨酸甲基化相互作用伴侣产生影响。
Polycomb-directed repression of gene expression is frequently misregulated in human diseases. A quantitative and target-specific cellular assay was utilized to discover the first potent positive allosteric modulator (PAM) peptidomimetic, UNC4976, of nucleic acid binding by CBX7, a chromodomain methyllysine reader of Polycomb repressive complex 1. The PAM activity of UNC4976 resulted in enhanced efficacy across three orthogonal cellular assays by simultaneously antagonizing H3K27me3-specific recruitment of CBX7 to target genes while increasing non-specific binding to DNA and RNA. PAM activity thereby reequilibrates PRC1 away from H3K27me3 target regions. Together, our discovery and characterization of UNC4976 not only revealed the most cellularly potent PRC1-specific chemical probe to date, but also uncovers a potential mechanism of Polycomb regulation with implications for non-histone lysine methylated interaction partners.