O-GlcNAc regulates gene expression by controlling detained intron splicing
O-GlcNAc regulates gene expression by controlling detained intron splicing
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DOI：
10.1093/nar/gkaa263
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发表时间：
2020-06-04
影响因子：
14.9
通讯作者：
Walker, Suzanne
中科院分区：
文献类型：
--
作者：
Tan, Zhi-Wei;Fei, George;Walker, Suzanne
前体rna中的内含子滞留有助于调节真核生物基因组中相当一部分基因的表达。内含子（DI）的剪接是如何被控制的，人们知之甚少。在这里，我们展示了一种普遍存在的称为O-GlcNAc的翻译后修饰，它被认为在营养条件波动时整合信号通路，控制被抑制的内含子剪接。利用安装O-GlcNAc的酶（O-GlcNAc transferase， OGT）和去除O-GlcNAc的酶（O-GlcNAcase， OGA）的特异性抑制剂，我们首次发现O-GlcNAc调节OGT和OGA中高度保守的内含子的剪接，以控制mRNA丰度，以缓冲O-GlcNAc的变化。我们表明，OGT和OGA代表了DI剪接如何控制基因表达的两种不同的范式。我们还发现，当O-GlcNAc循环基因的DI剪接无法恢复O-GlcNAc稳态时，内含子水平会发生全局变化。引人注目的是，当O-GlcNAc水平较低时，几乎所有滞留的内含子都能更有效地剪接，而其他可选的剪接途径变化最小。我们的研究结果表明，O-GlcNAc控制内含子剪接以调节全系统基因表达，提供了一种将营养条件与细胞转录机制相结合的方法。
Intron detention in precursor RNAs serves to regulate expression of a substantial fraction of genes in eukaryotic genomes. How detained intron (DI) splicing is controlled is poorly understood. Here, we show that a ubiquitous post-translational modification called O-GlcNAc, which is thought to integrate signaling pathways as nutrient conditions fluctuate, controls detained intron splicing. Using specific inhibitors of the enzyme that installs O-GlcNAc (O-GlcNAc transferase, or OGT) and the enzyme that removes O-GlcNAc (O-GlcNAcase, or OGA), we first show that O-GlcNAc regulates splicing of the highly conserved detained introns in OGT and OGA to control mRNA abundance in order to buffer O-GlcNAc changes. We show that OGT and OGA represent two distinct paradigms for how DI splicing can control gene expression. We also show that when DI splicing of the O-GlcNAc-cycling genes fails to restore O-GlcNAc homeostasis, there is a global change in detained intron levels. Strikingly, almost all detained introns are spliced more efficiently when O-GlcNAc levels are low, yet other alternative splicing pathways change minimally. Our results demonstrate that O-GlcNAc controls detained intron splicing to tune system-wide gene expression, providing a means to couple nutrient conditions to the cell's transcriptional regime.