Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation.
Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation.
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DOI：
10.1016/j.molcel.2015.02.029
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发表时间：
2015-04-16
期刊：
影响因子：
16
通讯作者：
Allis CD
中科院分区：
文献类型：
--
作者：
Sabari BR;Tang Z;Huang H;Yong-Gonzalez V;Molina H;Kong HE;Dai L;Shimada M;Cross JR;Zhao Y;Roeder RG;Allis CD
组蛋白在DNA调控元件上的乙酰化在转录激活中起着关键作用。组蛋白也被其他酰基部分修饰，包括巴豆酰基，但控制乙酰化与巴豆酰化的机制以及这种“选择”的功能后果仍不清楚。我们发现，共激活蛋白p300具有巴豆酰转移酶和乙酰转移酶的活动，p300催化的组蛋白巴豆酰化直接刺激转录比组蛋白乙酰化更大的程度。组蛋白巴豆酰化的水平受细胞内巴豆酰辅酶A浓度的调节，巴豆酰辅酶A的浓度可以通过遗传和环境干扰而改变。在基于细胞的转录激活模型中，增加或降低巴豆酰辅酶A的细胞浓度分别导致基因表达增强或减弱，这与活化基因的调控元件侧翼的组蛋白巴豆酰化水平相关。我们的研究结果支持了一个普遍的原则，其中差异组蛋白酰化（即乙酰化与巴豆酰化）夫妇细胞代谢的基因表达的调控。
Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that govern acetylation versus crotonylation and the functional consequences of this “choice” remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e. acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression.