Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop.
Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop.
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DOI：
10.1093/nar/gkv1015
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发表时间：
2015-11-16
影响因子：
14.9
通讯作者：
Stephens L
中科院分区：
文献类型：
--
作者：
Kiselev VY;Juvin V;Malek M;Luscombe N;Hawkins P;Le Novère N;Stephens L
PIP3是由第I类PI3K合成的，调节复杂的细胞反应，如生长和迁移。驱动细胞表型长期重塑的信号很难解决，因为复杂的反馈网络运行时间较长。依赖于PIP3的mRNA积累的调控显然在这一过程中很重要，但人们对此知之甚少。我们量化了未转化的乳腺上皮源性MCF10A细胞的全基因组mRNA谱及其对表皮生长因子急性调节的反应，在存在或不存在PI3Kα抑制剂的情况下，将其与癌症相关突变(表达PI3Kα等位基因或缺乏PIP3-磷酸酶/肿瘤抑制基因PTEN的同基因细胞)对PI3K信号的慢性激活进行比较。我们的结果表明，虽然许多mRNA会因PIP3信号的长期遗传扰动(“蝴蝶效应”)而改变，但有一小部分mRNA会随着不同的PIP3扰动而发生一致的变化。这暗示了更直接受调控的mRNAs的子集。我们发现，mRNAs对PIP3调控的特定方面做出了不同的反应。一些对PIP3敏感的mRNAs编码PI3K途径组分，因此暗示了转录反馈环。我们发现转录因子结合基序SRF和PRDM1是参与细胞运动的PIP3敏感mRNAs的重要调节因子。
PIP3 is synthesized by the Class I PI3Ks and regulates complex cell responses, such as growth and migration. Signals that drive long-term reshaping of cell phenotypes are difficult to resolve because of complex feedback networks that operate over extended times. PIP3-dependent modulation of mRNA accumulation is clearly important in this process but is poorly understood. We have quantified the genome-wide mRNA-landscape of non-transformed, breast epithelium-derived MCF10a cells and its response to acute regulation by EGF, in the presence or absence of a PI3Kα inhibitor, compare it to chronic activation of PI3K signalling by cancer-relevant mutations (isogenic cells expressing an oncomutant PI3Kα allele or lacking the PIP3-phosphatase/tumour-suppressor, PTEN). Our results show that whilst many mRNAs are changed by long-term genetic perturbation of PIP3 signalling (‘butterfly effect’), a much smaller number do so in a coherent fashion with the different PIP3 perturbations. This suggests a subset of more directly regulated mRNAs. We show that mRNAs respond differently to given aspects of PIP3 regulation. Some PIP3-sensitive mRNAs encode PI3K pathway components, thus suggesting a transcriptional feedback loop. We identify the transcription factor binding motifs SRF and PRDM1 as important regulators of PIP3-sensitive mRNAs involved in cell movement.