Iwase Shigeki, Lan Fei, Bayliss Peter, de la Torre-Ubieta Luis, Huarte Maite, Qi Hank H, Whetstine Johnathan R, Bonni Azad, Roberts Thomas M, Shi Yang
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2007 Mar 23;128(6):1077-88. doi: 10.1016/j.cell.2007.02.017. Epub 2007 Feb 22.
Histone methylation regulates chromatin structure and transcription. The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3). We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products. Other SMCX family members, including SMCY, RBP2, and PLU-1, also demethylated H3K4me3. SMCX bound H3K9me3 via its N-terminal PHD (plant homeodomain) finger, which may help coordinate H3K4 demethylation and H3K9 methylation in transcriptional repression. Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively. Importantly, studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity. Our findings thus identify a family of H3K4me3 demethylases and uncover a critical link between histone modifications and XLMR.
组蛋白甲基化调节染色质结构和转录。最近鉴定出的组蛋白去甲基化酶赖氨酸特异性去甲基化酶1（LSD1）在化学上仅局限于对单甲基化和二甲基化而非三甲基化的组蛋白H3赖氨酸4（H3K4me3）进行去甲基化。我们发现，编码一种JmjC结构域蛋白的X连锁智力迟钝（XLMR）基因SMCX（JARID1C）能将H3K4me3逆转为二甲基化和单甲基化产物，但不能使其转变为未甲基化产物。其他SMCX家族成员，包括SMCY、RBP2和PLU-1，也能对H3K4me3进行去甲基化。SMCX通过其N端的植物同源结构域（PHD）指结合H3K9me3，这可能有助于在转录抑制过程中协调H3K4去甲基化和H3K9甲基化。重要的是，一些XLMR患者的点突变分别降低了SMCX的去甲基化酶活性以及与H3K9me3肽段的结合能力。重要的是，斑马鱼和原代哺乳动物神经元研究表明，SMCX在神经元存活和树突发育中发挥作用，并且与去甲基化酶活性存在关联。因此，我们的研究结果鉴定出了一个H3K4me3去甲基化酶家族，并揭示了组蛋白修饰与XLMR之间的关键联系。
