Santos-Rosa Helena, Bannister Andrew J, Dehe Pierre M, Géli Vincent, Kouzarides Tony
Wellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge, CB2 1QR, United Kingdom.
J Biol Chem. 2004 Nov 12;279(46):47506-12. doi: 10.1074/jbc.M407949200. Epub 2004 Jul 27.
Set1p methylates lysine 4 of histone H3 and can activate transcription by recruiting the chromatin-remodeling factor Isw1p. In addition, Lys-4-methylated H3 is required for maintenance of silencing at the telomeres, rDNA, and HML locus in Saccharomyces cerevisiae. The molecular mechanism underlying the role of Set1p in silencing is not known. Here we report that euchromatic methylation of H3 Lys-4 is necessary to maintain silencing at specific heterochromatic sites. Inactivation of Set1p catalytic activity or mutation of H3 Lys-4 leads to decreased binding of the silent information regulator Sir3p at heterochromatic sites. Concomitantly, there is an increase in the amount of Sir3p bound to genes located in subtelomeric regions. Consistent with this result is the finding that in vitro, Sir3p preferentially binds histone H3 tails when methylation is absent at H3 Lys-4, a situation found in heterochromatin. The inability of Sir3p to bind methylated H3 Lys-4 tails suggests a model whereby H3 Lys-4 methylation prevents Sir3p association at euchromatic sites and therefore concentrates Sir3p at unmodified, heterochromatic regions of the genome.
Set1p使组蛋白H3的赖氨酸4位点发生甲基化，并可通过募集染色质重塑因子Isw1p来激活转录。此外，赖氨酸4甲基化的H3对于酿酒酵母端粒、核糖体DNA（rDNA）和HML位点的沉默维持是必需的。Set1p在沉默中发挥作用的分子机制尚不清楚。在此我们报告，H3赖氨酸4位点的常染色质甲基化对于维持特定异染色质位点的沉默是必要的。Set1p催化活性的失活或H3赖氨酸4位点的突变会导致沉默信息调节因子Sir3p在异染色质位点的结合减少。与此同时，与位于亚端粒区域的基因结合的Sir3p量增加。与该结果一致的是，在体外发现，当H3赖氨酸4位点不存在甲基化时（这是异染色质中的情况），Sir3p优先结合组蛋白H3尾巴。Sir3p无法结合甲基化的H3赖氨酸4尾巴提示了一种模型，即H3赖氨酸4甲基化阻止Sir3p在常染色质位点的结合，因此使Sir3p集中在基因组未修饰的异染色质区域。
