Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element
Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element
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激活依赖性 TRAF3 外显子 8 选择性剪接由与上游内含子元件结合的 CELF2 和 hnRNP C 控制
DOI：
10.1128/mcb.00488-16
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发表时间：
2017
影响因子：
5.3
通讯作者：
Heyd F
中科院分区：
文献类型：
--
作者：
Schultz A-S;Preussner M;Bunse M;Karni R;Heyd F
细胞类型特异性和诱导型可变剪接对调节基因表达和细胞功能具有根本性影响，包括在各种环境中的激活和分化。我们最近发现，激活诱导的TRAF 3外显子8跳跃激活非经典NF-κB信号在T细胞刺激，但这种剪接事件的调控基础仍然未知。在这里，我们确定顺式和反式调控元件，使这种剪接开关激活依赖和细胞类型特异性。顺式作用元件位于受调控外显子上游340至440个核苷酸处，并且以距离依赖性方式起作用，因为改变位置会降低其活性。一个小的干扰RNA筛选，然后通过交联免疫沉淀和突变分析，确定CELF 2和hnRNP C astrans的作用因子，直接结合的调控序列，并一起介导增加外显子跳跃在活化的T细胞。在几个模型系统中，CELF 2表达水平与TRAF 3外显子跳跃相关，表明CELF 2是决定性因素，hnRNP C是必要的，但不是足够的。这些数据表明CELF 2和hnRNP C之间的相互作用作为TRAF 3外显子8和其他外显子的激活依赖性选择性剪接的机制基础，并揭示了内含子剪接沉默子，其全部活性取决于受调控外显子上游300多个核苷酸的精确位置。
Cell-type-specific and inducible alternative splicing has a fundamental impact on regulating gene expression and cellular function in a variety of settings, including activation and differentiation. We have recently shown that activation-induced skipping of TRAF3 exon 8 activates noncanonical NF-κB signaling upon T cell stimulation, but the regulatory basis for this splicing event remains unknown. Here we identifycis- andtrans-regulatory elements rendering this splicing switch activation dependent and cell type specific. Thecis-acting element is located 340 to 440 nucleotides upstream of the regulated exon and acts in a distance-dependent manner, since altering the location reduces its activity. A small interfering RNA screen, followed by cross-link immunoprecipitation and mutational analyses, identified CELF2 and hnRNP C astrans-acting factors that directly bind the regulatory sequence and together mediate increased exon skipping in activated T cells. CELF2 expression levels correlate with TRAF3 exon skipping in several model systems, suggesting that CELF2 is the decisive factor, with hnRNP C being necessary but not sufficient. These data suggest an interplay between CELF2 and hnRNP C as the mechanistic basis for activation-dependent alternative splicing of TRAF3 exon 8 and additional exons and uncover an intronic splicing silencer whose full activity depends on the precise location more than 300 nucleotides upstream of the regulated exon.
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影响因子：
16.8
作者：
Lipp, Jesse J.;Marvin, Michael C.;Guthrie, Christine
通讯作者：
Guthrie, Christine
影响因子：
4.5
作者：
Martinez, Nicole M.;Pan, Qun;Lynch, Kristen W.
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Lynch, Kristen W.
节律性 U2af26 选择性剪接控制小鼠 PERIOD1 稳定性和生物钟
影响因子：
16
作者：
Preussner M;Wilhelmi I;Schultz A-S;Finkernagel F;Michel M;Moroy T;Heyd F
通讯作者：
Heyd F
影响因子：
16
作者：
Warzecha, Claude C.;Sato, Trey K.;Nabet, Behnam;Hogenesch, John B.;Carstens, Russ P.
通讯作者：
Carstens, Russ P.
影响因子：
10.5
作者：
Boutz, Paul L.;Stoilov, Peter;Black, Douglas L.
通讯作者：
Black, Douglas L.