Yang Yul W, Flynn Ryan A, Chen Yong, Qu Kun, Wan Bingbing, Wang Kevin C, Lei Ming, Chang Howard Y
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States.
Elife. 2014 Feb 12;3:e02046. doi: 10.7554/eLife.02046.
The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates. DOI: http://dx.doi.org/10.7554/eLife.02046.001.
MLL复合物的WDR5亚基维持活跃染色质并能结合RNA；这两种活性之间的关系尚不清楚。在此，我们确定了WDR5上的一个RNA结合口袋，并发现了一个WDR5突变体（F266A），该突变体可选择性地消除RNA结合，而不影响MLL复合物的组装或催化活性。在胚胎干细胞中的互补实验表明，WDR5 F266A突变体无法在染色质上积累，在基因激活、组蛋白H3赖氨酸4三甲基化的维持以及胚胎干细胞自我更新方面存在缺陷。我们鉴定出了一类与野生型WDR5相互作用但不与F266A突变体相互作用的胚胎干细胞信使RNA和长链非编码RNA，包括几种已知对胚胎干细胞基因表达很重要的长链非编码RNA。这些结果表明，特定的RNA是WDR5-MLL复合物维持活跃染色质状态和胚胎干细胞命运的重要组成部分。DOI: http://dx.doi.org/10.7554/eLife.02046.001
