Rea S, Eisenhaber F, O'Carroll D, Strahl B D, Sun Z W, Schmid M, Opravil S, Mechtler K, Ponting C P, Allis C D, Jenuwein T
Research Institute of Molecular Pathology, The Vienna Biocenter, Austria.
Nature. 2000 Aug 10;406(6796):593-9. doi: 10.1038/35020506.
The organization of chromatin into higher-order structures influences chromosome function and epigenetic gene regulation. Higher-order chromatin has been proposed to be nucleated by the covalent modification of histone tails and the subsequent establishment of chromosomal subdomains by non-histone modifier factors. Here we show that human SUV39H1 and murine Suv39h1--mammalian homologues of Drosophila Su(var)3-9 and of Schizosaccharomyces pombe clr4--encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity. Methylation of lysine 9 interferes with phosphorylation of serine 10, but is also influenced by pre-existing modifications in the amino terminus of H3. In vivo, deregulated SUV39H1 or disrupted Suv39h activity modulate H3 serine 10 phosphorylation in native chromatin and induce aberrant mitotic divisions. Our data reveal a functional interdependence of site-specific H3 tail modifications and suggest a dynamic mechanism for the regulation of higher-order chromatin.
染色质组装成高级结构影响染色体功能和表观遗传基因调控。有人提出，高级染色质由组蛋白尾部的共价修饰引发，并随后由非组蛋白修饰因子建立染色体亚结构域。我们在此表明，人类SUV39H1和小鼠Suv39h1（果蝇Su(var)3-9和粟酒裂殖酵母clr4在哺乳动物中的同源物）编码组蛋白H3特异性甲基转移酶，其在体外可选择性地将组蛋白H3氨基末端的赖氨酸9甲基化。我们将催化基序定位到进化上保守的SET结构域，该结构域需要相邻的富含半胱氨酸区域来赋予组蛋白甲基转移酶活性。赖氨酸9的甲基化会干扰丝氨酸10的磷酸化，但也受H3氨基末端预先存在的修饰影响。在体内，SUV39H1失调或Suv39h活性破坏会调节天然染色质中H3丝氨酸10的磷酸化，并诱导异常有丝分裂。我们的数据揭示了位点特异性H3尾部修饰之间的功能相互依赖性，并提出了一种调控高级染色质的动态机制。
