Identification of Novel Targets of RBM5 in the Healthy and Injured Brain.
Identification of Novel Targets of RBM5 in the Healthy and Injured Brain.
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DOI：
10.1016/j.neuroscience.2020.04.024
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发表时间：
2020-08-01
期刊：
影响因子：
3.3
通讯作者：
Kochanek PM
中科院分区：
文献类型：
--
作者：
Jackson TC;Janesko-Feldman K;Gorse K;Vagni VA;Jackson EK;Kochanek PM
肿瘤抑制因子RNA结合基序5（RBM 5）以组织特异性方式调节所选一组mRNA的表达水平和盒外显子定义（即剪接）。大多数RBM 5调节的靶点是在肿瘤学研究中鉴定的，并且经常涉及介导凋亡性细胞死亡的基因。关于RBM 5在大脑中的作用知之甚少。此外，目前还不清楚是否需要脑损伤来检测RBM 5介导的对促凋亡基因的影响，因为在基线时，健康成人CNS中的促凋亡基因的表达水平较低。产生条件性/floxed（脑特异性）基因删除小鼠以阐明CNS特异性RBM 5 mRNA靶标。使雄性/雌性小鼠经受严重的受控皮质撞击（CCI）创伤性脑损伤（TBI），以增加促死亡mRNA的背景表达并促进RBM 5抑制降低CNS中半胱天冬酶/FAS的损伤后上调的假设的测试。正如预期的那样，CCI增加了受损皮质中的半胱天冬酶/FAS mRNA。RBM 5 KO不影响它们的水平或剪接。令人惊讶的是，KO增加了新靶点的mRNA水平，包括酪蛋白激酶2 α相互作用蛋白（Csnka 2 ip/CKT 2）-一种被认为在大脑中不表达的基因，与这里的发现相反。在科斯中还检测到22个独特的剪接事件，包括在调节突触膜胞吐2（Rims 2）中增加的盒外显子20-22的嵌段包含。总之，在这里，我们对健康和受伤的RBM 5 KO小鼠脑组织进行了全基因组转录组分析，以阐明CNS中这种神秘的RBP的第一个已知基因靶点。
The tumor suppressor RNA-binding motif 5 (RBM5) regulates the expression levels and cassette exon-definition (i.e. splicing) of a select set of mRNAs in a tissue-specific manner. Most RBM5-regulated targets were identified in oncological investigations and frequently involve genes which mediate apoptotic cell death. Little is known about the role of RBM5 in the brain. Also, it is unclear if a brain injury may be required to detect RBM5 mediated effects on pro-apoptotic genes due to their low expression levels in the healthy adult CNS at baseline. Conditional/floxed (brain-specific) gene deleter mice were generated to elucidate CNS-specific RBM5 mRNA targets. Male/female mice were subjected to a severe controlled cortical impact (CCI) traumatic brain injury (TBI) in order to increase the background expression of pro-death mRNAs and facilitate testing of the hypothesis that RBM5 inhibition decreases post-injury upregulation of caspases/FAS in the CNS. As expected, a CCI increased caspases/FAS mRNA in the injured cortex. RBM5 KO did not affect their levels or splicing. Surprisingly, KO increased the mRNA levels of novel targets including casein kinase 2 alpha prime interacting protein (Csnka2ip/CKT2) – a gene not thought to be expressed in the brain, contrary to findings here. Twenty-two unique splicing events were also detected in KOs including increased block-inclusion of cassette exons 20–22 in regulating synaptic membrane exocytosis 2 (Rims2). In conclusion, here we used genome-wide transcriptomic analysis on healthy and injured RBM5 KO mouse brain tissue to elucidate the first known gene targets of this enigmatic RBP in this CNS.
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DOI：
10.3233/jad-180726
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Chen M;Song H;Cui J;Johnson CE;Hubler GK;DePalma RG;Gu Z;Xia W
通讯作者：
Xia W
影响因子：
3.4
作者：
Hook G;Jacobsen JS;Grabstein K;Kindy M;Hook V
通讯作者：
Hook V
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
48
作者：
Bazarian, Jeffrey J.;Biberthaler, Peter;Jagoda, Andy S.
通讯作者：
Jagoda, Andy S.
影响因子：
2.3
作者：
Kim, Ki-Tack;Lee, Jong Seok;Chung, Joo-Ho
通讯作者：
Chung, Joo-Ho