Division of Molecular Biology of the Cell II, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg, Germany.
Nat Struct Mol Biol. 2010 Apr;17(4):445-50. doi: 10.1038/nsmb.1778. Epub 2010 Mar 7.
Histone lysine methylation is dynamically regulated by lysine methyltransferases and lysine demethylases. Here we show that PHD finger protein 8 (PHF8), a protein containing a PHD finger and a Jumonji C (JmjC) domain, is associated with hypomethylated rRNA genes (rDNA). PHF8 interacts with the RNA polymerase I transcription machinery and with WD repeat-containing protein 5 (WDR5)-containing H3K4 methyltransferase complexes. PHF8 exerts a positive effect on rDNA transcription, with transcriptional activation requiring both the JmjC domain and the PHD finger. PHF8 demethylates H3K9me1/2, and its catalytic activity is stimulated by adjacent H3K4me3. A point mutation within the JmjC domain that is linked to mental retardation with cleft lip and palate (XLMR-CL/P) abolishes demethylase activity and transcriptional activation. Though further work is needed to unravel the contribution of PHF8 activity to mental retardation and cleft lip/palate, our results reveal a functional interplay between H3K4 methylation and H3K9me1/2 demethylation, linking dynamic histone methylation to rDNA transcription and neural disease.
组蛋白赖氨酸甲基化受赖氨酸甲基转移酶和赖氨酸去甲基酶的动态调控。在这里，我们发现含有 PHD 指结构域和 Jumonji C（JmjC）结构域的 PHF8 蛋白与低甲基化 rRNA 基因（rDNA）有关。PHF8 与 RNA 聚合酶 I 转录机制以及含有 WD 重复的蛋白 5（WDR5）的 H3K4 甲基转移酶复合物相互作用。PHF8 对 rDNA 转录具有正向影响，转录激活需要 JmjC 结构域和 PHD 指结构域。PHF8 可以使 H3K9me1/2 去甲基化，其催化活性受相邻 H3K4me3 的刺激。与唇腭裂伴智力障碍（XLMR-CL/P）相关的 JmjC 结构域内的点突变会使去甲基酶活性和转录激活丧失。虽然还需要进一步的工作来阐明 PHF8 活性对智力障碍和唇腭裂的贡献，但我们的结果揭示了 H3K4 甲基化和 H3K9me1/2 去甲基化之间的功能相互作用，将动态组蛋白甲基化与 rDNA 转录和神经疾病联系起来。
