Multi-omics analysis reveals regulators of the response to PDGF-BB treatment in pulmonary artery smooth muscle cells.
Multi-omics analysis reveals regulators of the response to PDGF-BB treatment in pulmonary artery smooth muscle cells.
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多组学分析揭示了肺动脉平滑肌细胞对 PDGF-BB 治疗反应的调节因子。
DOI：
10.1186/s12864-016-3122-3
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发表时间：
2016-10-06
期刊：
影响因子：
4.4
通讯作者：
Gou D
中科院分区：
文献类型：
--
作者：
Chen J;Cui X;Qian Z;Li Y;Kang K;Qu J;Li L;Gou D
肺动脉高压（PAH）是一种由于细胞异常增殖导致肺血管明显狭窄的致死性疾病。血小板衍生生长因子BB（PDGF-BB）是一种有效的平滑肌细胞增殖的促分裂原。 为了更好地了解这种生长因子如何调节肺动脉平滑肌细胞（PASMCs）增殖，我们试图在全系统水平上表征对PDGF-BB刺激的反应，包括转录组和蛋白质组。在这项研究中，我们确定了1611个mRNA（转录组），207个蛋白质（蛋白质组）差异表达的PASMCs响应PDGF-BB刺激的基础上RNA测序和同量异序标签的相对和绝对定量（iTRAQ）测定。转录因子-靶点网络分析显示PDGF-BB可能通过HIF 1A、JUN、EST 1、ETS 1、SMAD 1、FOS、SP 1、STAT 1、LEF 1和CEBPB等转录因子调控基因表达。其中SMAD 1参与的BMPR 2/SMADs轴在PAH的发生发展中起重要作用。有趣的是，我们观察到BMPR 2的表达在mRNA和蛋白水平上均响应于PDGF-BB而降低。进一步的研究表明，BMPR 2是miR-376 b的直接靶标，其在PDGF-BB处理后上调。EdU掺入实验显示miR-376 b促进PASMCs增殖。首次在正常PASMCs中进行了PDGF-BB调节的转录组和蛋白质组的整合分析，这揭示了PDGF信号传导与BMPR 2/SMADs轴之间的串扰。进一步的研究表明，PDGF-BB诱导miR-376 b表达上调介导BMPR 2表达下调，导致其下游靶基因表达改变，促进PASMCs增殖。本文的在线版本（doi：10.1186/s12864-016-3122-3）包含补充材料，可供授权用户使用。
Pulmonary arterial hypertension (PAH) is a lethal disease with pronounced narrowing of pulmonary vessels due to abnormal cell proliferation. The platelet-derived growth factor BB (PDGF-BB) is well known as a potent mitogen for smooth muscle cell proliferation. To better understand how this growth factor regulates pulmonary arterial smooth muscle cells (PASMCs) proliferation, we sought to characterize the response to PDGF-BB stimulation at system-wide levels, including the transcriptome and proteome. In this study, we identified 1611 mRNAs (transcriptome), 207 proteins (proteome) differentially expressed in response to PDGF-BB stimulation in PASMCs based on RNA-sequencing and isobaric tags for relative and absolute quantification (iTRAQ) assay. Transcription factor (TF)-target network analysis revealed that PDGF-BB regulated gene expression potentially via TFs including HIF1A, JUN, EST1, ETS1, SMAD1, FOS, SP1, STAT1, LEF1 and CEBPB. Among them, SMAD1-involved BMPR2/SMADs axis plays a significant role in PAH development. Interestingly, we observed that the expression of BMPR2 was decreased in both mRNA and protein level in response to PDGF-BB. Further study revealed that BMPR2 is the direct target of miR-376b that is up-regulated upon PDGF-BB treatment. Finally, EdU incorporation assay showed that miR-376b promoted proliferation of PASMCs. This integrated analysis of PDGF-BB-regulated transcriptome and proteome was performed for the first time in normal PASMCs, which revealed a crosstalk between PDGF signaling and BMPR2/SMADs axis. Further study demonstrated that PDGF-BB-induced miR-376b upregulation mediated the downregulation of BMPR2, which led to expression change of its downstream targets and promoted proliferation of PASMCs. The online version of this article (doi:10.1186/s12864-016-3122-3) contains supplementary material, which is available to authorized users.
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影响因子：
5.8
作者：
Mermis J;Gu H;Xue B;Li F;Tawfik O;Buch S;Bartolome S;O'Brien-Ladner A;Dhillon NK
通讯作者：
Dhillon NK
影响因子：
46.9
作者：
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影响因子：
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作者：
Hansmann, Georg;de Jesus Perez, Vinicio A.;Rabinovitch, Marlene
通讯作者：
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影响因子：
2.7
作者：
Pellegrino, Sara;Ferri, Nicola;Cabrele, Chiara
通讯作者：
Cabrele, Chiara
DOI：
10.1152/ajplung.00316.2011
发表时间：
2012-03-01
影响因子：
4.9
作者：
Yang, Shanzhong;Banerjee, Sami;Liu, Gang
通讯作者：
Liu, Gang