Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3.
Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3.
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DOI：
10.1007/s11033-015-3882-x
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发表时间：
2015-09
影响因子：
2.8
通讯作者：
Agrawal DK
中科院分区：
文献类型：
--
作者：
Boosani CS;Dhar K;Agrawal DK
先前我们发现，在动脉粥样硬化的微型猪进行球囊血管成形术后，新内膜增生性区SOCS3的表达降低。在我们最近使用人冠状动脉平滑肌细胞（HCASMC）进行的体外研究中，我们观察到TNF-α和IGF-1存在时对SOCS3表达的抑制，这与微猪体内的研究结果相关。我们还报道了两个独立的机制，JAK/STAT3/NFκB和SOCS3的启动子甲基化是TNF-α -和igf -1诱导的SOCS3抑制的原因。在这项研究中，我们利用miRNA阵列和基因表达方法，探索了上述SOCS3抑制的分子机制，并鉴定了几个与SOCS3表达调控相关的miRNA。我们的miRNA表达谱显示，hsa-miR-758和hsa-miR-1264这两种特异性miRNA的表达深度下调，当HCASMCs同时接受TNF-α和IGF-1处理时，它们的表达水平下降了8-10倍。与此同时，hsa-miR-155、hsa-miR-146b-5p和hsa-miR-146a这三种特异性mirna的表达水平显著上调，表达水平增加了约3-7倍。重要的是，我们还发现miRNA hsa-miR-1264通过结合DNA甲基转移酶-1 （DNMT1）的3'UTR区域来影响其表达，从而靶向DNA甲基转移酶-1 （DNMT1）转录物。hsa-miR-1264在HCASMCs中的表达不仅导致DNMT1 mRNA转录减少，而且还增加了SOCS3的表达。TNF-α和IGF-1治疗导致hsa-miR-1264水平急剧下降，而DNMT1的表达没有变化。因此，DNMT1活性引起SOCS3启动子区CpG岛的超甲基化，并抑制其表达。这可能是一种与TNF-α -和igf -1诱导的平滑肌细胞增殖有关的致病表观遗传机制，参与了冠状动脉增生和再狭窄的发病机制。
Previously we found decreased expression of SOCS3 in neointimal hyperplastic region following balloon angioplasty in atherosclerotic micro swine. In our recent in vitro studies using human coronary artery smooth muscle cells (HCASMC), we observed the inhibition of SOCS3 expression in the presence of both TNF-α and IGF-1, correlating with the in-vivo findings in microswine. We also reported that two independent mechanisms, JAK/STAT3/NFκB and promoter methylation of SOCS3 were responsible for TNF-α– and IGF-1-induced SOCS3 inhibition. In this study, using miRNA array and gene expression approaches, we explored the molecular mechanisms involved in the above SOCS3 repression and identified several miRNAs that are associated with the regulation of SOCS3 expression. Our miRNA expression profiling revealed profound down-regulation of two specific miRNAs, hsa-miR-758 and hsa-miR-1264, whose expression levels decreased by 8–10 folds when HCASMCs were treated with both TNF-α and IGF-1. This was accompanied with a significant up-regulation of three specific miRNAs, hsa-miR-155, hsa-miR-146b-5p and hsa-miR-146a, which showed about 3–7 fold increases in their expression levels. Importantly, we also found that the miRNA hsa-miR-1264 targets DNA methyltransferase-1 (DNMT1) transcripts by binding to its 3’UTR region to affect its expression. Expression of hsa-miR-1264 in HCASMCs not only resulted in decreased DNMT1 mRNA transcripts but it also increased SOCS3 expression. The treatment with TNF-α and IGF-1 resulted in drastic decrease in hsa-miR-1264 levels with no change in the expression of DNMT1. Consequently, the DNMT1 activity caused hypermethylation in the CpG island of the SOCS3 promoter region and inhibited its expression. This could be a causative epigenetic mechanism associated with TNF-α– and IGF-1-induced smooth muscle cell proliferation involved in the pathogenesis of coronary artery hyperplasia and restenosis.
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影响因子：
14.9
作者：
Thomson DW;Bracken CP;Goodall GJ
通讯作者：
Goodall GJ
DOI：
10.4161/cc.25548
发表时间：
2013-07-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Persson JL
通讯作者：
Persson JL
影响因子：
14.9
作者：
Kozomara A;Griffiths-Jones S
通讯作者：
Griffiths-Jones S
影响因子：
13.5
作者：
Braconi, Chiara;Huang, Nianyuan;Patel, Tushar
通讯作者：
Patel, Tushar
影响因子：
14.9
作者：
Griffiths-Jones, S
通讯作者：
Griffiths-Jones, S