The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases
The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases
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DOI：
10.1016/j.cell.2007.02.017
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发表时间：
2007-03-23
期刊：
影响因子：
64.5
通讯作者：
Shi, Yang
中科院分区：
文献类型：
--
作者：
Iwase, Shigeki;Lan, Fei;Shi, Yang
组蛋白甲基化调节染色质结构和转录。最近鉴定的组蛋白去甲基化酶赖氨酸特异性去甲基化酶 1 (LSD1) 在化学上仅限于单甲基化和二甲基化组蛋白 H3 赖氨酸 4 (H3K4me3)，但不能去甲基化三甲基化。我们发现编码 JmjC 结构域蛋白的 X 连锁智力迟钝 (XLMR) 基因 SMCX (JARID1C) 可将 H3K4me3 逆转为二甲基化和单甲基化产物，但不会逆转未甲基化产物。其他 SMCX 家族成员，包括 SMCY、RBP2 和 PLU-1，也使 H3K4me3 去甲基化。 SMCX 通过其 N 端 PHD（植物同源域）指结合 H3K9me3，这可能有助于协调转录抑制中的 H3K4 去甲基化和 H3K9 甲基化。值得注意的是，几个 XLMR 患者点突变分别降低了 SMCX 去甲基酶活性和与 H3K9me3 肽的结合。重要的是，对斑马鱼和初级哺乳动物神经元的研究证明了 SMCX 在神经元存活和树突发育中的作用以及与去甲基酶活性的联系。因此，我们的研究结果鉴定了 H3K4me3 去甲基酶家族，并揭示了组蛋白修饰和 XLMR 之间的关键联系。
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 tri-methylated 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.