Sequence and tissue targeting specificity of ZFP36L2 reveals Elavl2 as a novel target with co-regulation potential.
Sequence and tissue targeting specificity of ZFP36L2 reveals Elavl2 as a novel target with co-regulation potential.
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ZFP 36L2的序列和组织靶向特异性揭示Elavl2是具有共调节潜力的新靶标。
DOI：
10.1093/nar/gkac209
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发表时间：
2022-04-22
影响因子：
14.9
通讯作者：
Ramos, Silvia B., V
中科院分区：
文献类型：
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作者：
Redmon, Ian C.;Ardizzone, Matthew;Hekimoglu, Hilal;Hatfield, Breanne M.;Waldern, Justin M.;Dey, Abhishek;Montgomery, Stephanie A.;Laederach, Alain;Ramos, Silvia B., V
锌指蛋白36样2（ZFP 36 L2）是一种RNA结合蛋白，其使含有腺嘌呤-尿苷富集元件（战神）的转录物不稳定。不同组织中ZFP 36 L2靶标之间的重叠最小，表明ZFP 36 L2靶向具有高度组织特异性。我们开发了一种新的Zfp 36 l2缺乏小鼠模型（L2-fKO），以确定控制这种组织特异性的因素。我们通过RNA-seq在L2-fKO脾中发现了549个上调的基因。这些上调的基因在3′ UTR的ARE基序中富集，这表明它们是ZFP 36 L2靶点，然而，仅从基序分析来看，靶向的精确序列要求并不明显。因此，我们对12个新的推定靶点进行了凝胶迁移率测定，并确定ZFP 36 L2需要7聚体（UAUUUAU）基序进行结合。我们观察到上调基因中7聚体ARE基序的统计学显著富集，并确定ZFP 36 L2靶标富集多个7聚体基序。具有三个7聚体（UAUUUAU）基序的Elavl 2 mRNA在L2-fKO脾中也上调。ZFP 36 L2的过表达，而不是ZFP 36 L2（C176 S）突变体，降低了Elavl 2 mRNA表达，表明直接的负面影响。此外，报告基因测定证明ZFP 36 L2对Elavl 2衰变的作用依赖于Elavl 2 -3′UTR，并且需要7-mer战神。我们的数据表明Elavl 2 mRNA是ZFP 36 L2的新靶点，特异于脾脏。ZFP 36 L2与其他RNA结合蛋白（如ELAVL 2）结合可能会控制组织特异性。通过ZFP 36 L2和ELAVL 2调节Elavl 2 mRNA。在WT中ZFP 36 L2优于ELAVL 2。自身正反馈环可能在ZFP 36 L2-fKO中占主导地位，有利于ELAVL 2对其自身转录物的影响。
Zinc finger protein 36 like 2 (ZFP36L2) is an RNA-binding protein that destabilizes transcripts containing adenine-uridine rich elements (AREs). The overlap between ZFP36L2 targets in different tissues is minimal, suggesting that ZFP36L2-targeting is highly tissue specific. We developed a novel Zfp36l2-lacking mouse model (L2-fKO) to identify factors governing this tissue specificity. We found 549 upregulated genes in the L2-fKO spleen by RNA-seq. These upregulated genes were enriched in ARE motifs in the 3′UTRs, which suggests that they are ZFP36L2 targets, however the precise sequence requirement for targeting was not evident from motif analysis alone. We therefore used gel-shift mobility assays on 12 novel putative targets and established that ZFP36L2 requires a 7-mer (UAUUUAU) motif to bind. We observed a statistically significant enrichment of 7-mer ARE motifs in upregulated genes and determined that ZFP36L2 targets are enriched for multiple 7-mer motifs. Elavl2 mRNA, which has three 7-mer (UAUUUAU) motifs, was also upregulated in L2-fKO spleens. Overexpression of ZFP36L2, but not a ZFP36L2(C176S) mutant, reduced Elavl2 mRNA expression, suggesting a direct negative effect. Additionally, a reporter assay demonstrated that the ZFP36L2 effect on Elavl2 decay is dependent on the Elavl2-3′UTR and requires the 7-mer AREs. Our data indicate that Elavl2 mRNA is a novel target of ZFP36L2, specific to the spleen. Likely, ZFP36L2 combined with other RNA binding proteins, such as ELAVL2, governs tissue specificity. Elavl2 mRNA modulation by ZFP36L2 and ELAVL2. ZFP36L2 prevails over ELAVL2 in WT. Auto-positive feedback loop likely predominates in ZFP36L2-fKO favoring ELAVL2 effects on its own transcript.
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影响因子：
14.9
作者：
Cook KB;Kazan H;Zuberi K;Morris Q;Hughes TR
通讯作者：
Hughes TR
影响因子：
4.5
作者：
Ball, Christopher B.;Solem, Amanda C.;Ramos, Silvia B. V.
通讯作者：
Ramos, Silvia B. V.
影响因子：
4.8
作者：
Lai, WS;Carballo, E;Blackshear, PJ
通讯作者：
Blackshear, PJ
影响因子：
14.9
作者：
Kiesel A;Roth C;Ge W;Wess M;Meier M;Söding J
通讯作者：
Söding J
影响因子：
--
作者：
Duan, Haichuan;Cherradi, Nadia;Jefcoate, Colin
通讯作者：
Jefcoate, Colin