Department of Genetics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):E627-35. doi: 10.1073/pnas.1103344108. Epub 2011 Aug 1.
Recent studies have provided strong evidence for a regulatory link among chromatin structure, histone modification, and splicing regulation. However, it is largely unknown how local histone modification patterns surrounding alternative exons are connected to differential alternative splicing outcomes. Here we show that splicing regulator Hu proteins can induce local histone hyperacetylation by association with their target sequences on the pre-mRNA surrounding alternative exons of two different genes. In both primary and mouse embryonic stem cell-derived neurons, histone hyperacetylation leads to an increased local transcriptional elongation rate and decreased inclusion of these exons. Furthermore, we demonstrate that Hu proteins interact with histone deacetylase 2 and inhibit its deacetylation activity. We propose that splicing regulators may actively modulate chromatin structure when recruited to their target RNA sequences cotranscriptionally. This "reaching back" interaction with chromatin provides a means to ensure accurate and efficient regulation of alternative splicing.
最近的研究为染色质结构、组蛋白修饰和剪接调控之间的调控联系提供了有力的证据。然而，目前还不清楚周围的替代外显子的局部组蛋白修饰模式如何与不同的选择性剪接结果相关联。在这里，我们显示剪接调节剂 Hu 蛋白可以通过与它们在两个不同基因的前 mRNA 中围绕替代外显子的靶序列结合，诱导局部组蛋白超乙酰化。在原代和小鼠胚胎干细胞衍生的神经元中，组蛋白超乙酰化导致局部转录延伸速率增加，这些外显子的包含减少。此外，我们证明 Hu 蛋白与组蛋白去乙酰化酶 2 相互作用并抑制其去乙酰化活性。我们提出，当剪接调节剂被招募到其靶 RNA 序列时，它们可能会在转录过程中主动调节染色质结构。这种与染色质的“回溯”相互作用提供了一种确保选择性剪接准确和有效的调节的方法。
