Chromatin-mediated alternative splicing regulates cocaine-reward behavior.
Chromatin-mediated alternative splicing regulates cocaine-reward behavior.
复制标题
DOI：
10.1016/j.neuron.2021.08.008
复制
发表时间：
2021-09-15
期刊：
影响因子：
16.2
通讯作者：
Heller EA
中科院分区：
文献类型：
--
作者：
Xu SJ;Lombroso SI;Fischer DK;Carpenter MD;Marchione DM;Hamilton PJ;Lim CJ;Neve RL;Garcia BA;Wimmer ME;Pierce RC;Heller EA
神经元可变剪接是大脑中一种关键的基因调控机制。然而，剪接体机制不足以完全确定剪接的复杂性。在考虑表观基因组在活动依赖性可变剪接中的作用时，我们和其他研究人员发现组蛋白修饰H3K36me3是一种可能的剪接调节因子。在当前的研究中，我们发现小鼠自我给予可卡因会导致广泛的差异可变剪接，同时在差异剪接位点处H3K36me3富集。重要的是，只有靶向表观遗传编辑才能区分H3K36me3在剪接中的直接作用和通过调控基因组其他位置的剪接因子表达所产生的间接作用。我们以Srsf11为靶点，在小鼠自我给予可卡因后，该基因在大脑中既发生可变剪接，又有H3K36me3富集。对Srsf11上的H3K36me3进行表观遗传编辑足以驱动其可变剪接，并增强小鼠自我给予可卡因的行为，从而确定了H3K36me3与Srsf11的可变剪接以及奖赏行为之间的直接因果关系。
滥用药物，如可卡因，通过组蛋白修饰的变化来调控神经元基因表达。徐等人应用表观遗传编辑确定了组蛋白修饰H3K36me3在剪接因子基因Srsf11的可变剪接以及可卡因奖赏行为调控中的新作用。
Neuronal alternative splicing is a key gene regulatory mechanism in brain. Yet the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification, H3K36me3, to be a putative splicing regulator. In the current study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior. Drugs of abuse, such as cocaine, regulate neuronal gene expression through changes in histone modifications. Xu et al apply epigenetic editing to define a novel role for the histone modification, H3K36me3, in alternative splicing of splice factor gene, Srsf11, and regulation of cocaine reward behavior.
登录
查看更多内容
影响因子：
16.8
作者：
de Almeida, Sergio Fernandes;Grosso, Ana Rita;Carmo-Fonseca, Maria
通讯作者：
Carmo-Fonseca, Maria
影响因子：
5.1
作者：
Buchta, William C.;Moutal, Aubin;Riegel, Arthur C.
通讯作者：
Riegel, Arthur C.
影响因子：
12.3
作者：
Feng J;Wilkinson M;Liu X;Purushothaman I;Ferguson D;Vialou V;Maze I;Shao N;Kennedy P;Koo J;Dias C;Laitman B;Stockman V;LaPlant Q;Cahill ME;Nestler EJ;Shen L
通讯作者：
Shen L
影响因子：
64.5
作者：
Bonev B;Mendelson Cohen N;Szabo Q;Fritsch L;Papadopoulos GL;Lubling Y;Xu X;Lv X;Hugnot JP;Tanay A;Cavalli G
通讯作者：
Cavalli G
影响因子：
16.6
作者：
Carpenter, Marco D.;Hu, Qiwen;Heller, Elizabeth A.
通讯作者：
Heller, Elizabeth A.