Wysocka Joanna, Swigut Tomek, Milne Thomas A, Dou Yali, Zhang Xin, Burlingame Alma L, Roeder Robert G, Brivanlou Ali H, Allis C David
Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10021, USA.
Cell. 2005 Jun 17;121(6):859-72. doi: 10.1016/j.cell.2005.03.036.
Histone H3 lysine 4 (K4) methylation has been linked to the transcriptional activation in a variety of eukaryotic species. Here we show that a common component of MLL1, MLL2, and hSet1 H3 K4 methyltransferase complexes, the WD40-repeat protein WDR5, directly associates with histone H3 di- and trimethylated at K4 and with H3-K4-dimethylated nucleosomes. WDR5 is required for binding of the methyltransferase complex to the K4-dimethylated H3 tail as well as for global H3 K4 trimethylation and HOX gene activation in human cells. WDR5 is essential for vertebrate development, in that WDR5-depleted X. laevis tadpoles exhibit a variety of developmental defects and abnormal spatial Hox gene expression. Our results are the first demonstration that a WD40-repeat protein acts as a module for recognition of a specific histone modification and suggest a mechanism for reading and writing an epigenetic mark for gene activation.
组蛋白H3赖氨酸4（K4）甲基化与多种真核生物物种的转录激活相关。在此我们表明，MLL1、MLL2和hSet1 H3 K4甲基转移酶复合物的一个共同组分，WD40重复蛋白WDR5，直接与在K4处二甲基化和三甲基化的组蛋白H3以及与H3-K4-二甲基化核小体结合。WDR5是甲基转移酶复合物与K4-二甲基化H3尾部结合所必需的，也是人类细胞中整体H3 K4三甲基化和HOX基因激活所必需的。WDR5对脊椎动物发育至关重要，因为WDR5缺失的非洲爪蟾蝌蚪表现出多种发育缺陷和异常的空间Hox基因表达。我们的结果首次证明了WD40重复蛋白作为识别特定组蛋白修饰的模块，并提出了一种读取和写入用于基因激活的表观遗传标记的机制。
