Beta cell 5'-shifted isomiRs are candidate regulatory hubs in type 2 diabetes.
Beta cell 5'-shifted isomiRs are candidate regulatory hubs in type 2 diabetes.
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DOI：
10.1371/journal.pone.0073240
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sethupathy P
中科院分区：
文献类型：
--
作者：
Baran-Gale J;Fannin EE;Kurtz CL;Sethupathy P
小RNA的下一代深度测序揭示了微小RNA（miRNA）转录组的复杂性，这在很大程度上是由于miRNA序列变体（“isomiR”）的多样性。改变miRNA的种子序列（核苷酸2-8），包括改变起始位置，可以将靶向重定向到一组截然不同的RNA并改变生物学功能。我们对来自小鼠胰岛素瘤（MIN 6）细胞（广泛用作胰腺β细胞研究的替代物）的小RNA进行了深度测序，并开发了一种生物信息学分析管道来分析isomiR多样性。此外，我们将该管道应用于最近发表的来自原代人类β细胞和整个胰岛的小RNA-seq数据，并将miRNA谱与MIN 6的miRNA谱进行比较。我们发现：（1）MIN 6细胞中的miRNA表达谱与原代人β细胞和整个胰岛中的miRNA表达谱高度相关;（2）miRNA基因座可以产生具有不同5′-起始位置的多个高表达的isomiR（5′-isomiR）;（3）具有移位的起始位置的isomiR（5′-移位的isomiR）是高表达的，并且可以与它们的未移位的对应物（5′-参考miRNA）一样丰富。最后，我们确定了10个β细胞miRNA家族作为2型糖尿病（T2 D）基因网络中的候选调控中心。最重要的候选枢纽是miR-29，我们证明它调节对β细胞功能至关重要并与T2 D有关的几个基因的mRNA水平。其中三个候选miRNA枢纽是新的5′-移位异构体miR：miR-375+1，miR-375-1和miR-183- 5 p +1。我们通过计算机模拟靶点预测和体外转染研究表明，与典型的miR-375相比，miR-375+1和miR-375-1都可能靶向重叠但不同的β细胞基因组。总之，本研究首次描述了β细胞中的isomiR谱，并强调了5′-移位isomiR与T2 D的潜在功能相关性。
Next-generation deep sequencing of small RNAs has unveiled the complexity of the microRNA (miRNA) transcriptome, which is in large part due to the diversity of miRNA sequence variants (“isomiRs”). Changes to a miRNA’s seed sequence (nucleotides 2–8), including shifted start positions, can redirect targeting to a dramatically different set of RNAs and alter biological function. We performed deep sequencing of small RNA from mouse insulinoma (MIN6) cells (widely used as a surrogate for the study of pancreatic beta cells) and developed a bioinformatic analysis pipeline to profile isomiR diversity. Additionally, we applied the pipeline to recently published small RNA-seq data from primary human beta cells and whole islets and compared the miRNA profiles with that of MIN6. We found that: (1) the miRNA expression profile in MIN6 cells is highly correlated with those of primary human beta cells and whole islets; (2) miRNA loci can generate multiple highly expressed isomiRs with different 5′-start positions (5′-isomiRs); (3) isomiRs with shifted start positions (5′-shifted isomiRs) are highly expressed, and can be as abundant as their unshifted counterparts (5′-reference miRNAs). Finally, we identified 10 beta cell miRNA families as candidate regulatory hubs in a type 2 diabetes (T2D) gene network. The most significant candidate hub was miR-29, which we demonstrated regulates the mRNA levels of several genes critical to beta cell function and implicated in T2D. Three of the candidate miRNA hubs were novel 5′-shifted isomiRs: miR-375+1, miR-375-1 and miR-183-5p+1. We showed by in silico target prediction and in vitro transfection studies that both miR-375+1 and miR-375-1 are likely to target an overlapping, but distinct suite of beta cell genes compared to canonical miR-375. In summary, this study characterizes the isomiR profile in beta cells for the first time, and also highlights the potential functional relevance of 5′-shifted isomiRs to T2D.
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影响因子：
14.9
作者：
Kozomara A;Griffiths-Jones S
通讯作者：
Griffiths-Jones S
DOI：
10.1016/j.bbrc.2012.08.082
发表时间：
2012-09-21
影响因子：
3.1
作者：
Bagge, Annika;Clausen, Trine R.;Dalgaard, Louise T.
通讯作者：
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影响因子：
14.9
作者：
Burroughs AM;Kawano M;Ando Y;Daub CO;Hayashizaki Y
通讯作者：
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影响因子：
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作者：
Alon S;Mor E;Vigneault F;Church GM;Locatelli F;Galeano F;Gallo A;Shomron N;Eisenberg E
通讯作者：
Eisenberg E
DOI：
10.1073/pnas.0800334105
发表时间：
2008-06-10
影响因子：
11.1
作者：
Azuma-Mukai, Asuka;Oguri, Hideo;Siomi, Mikiko C.
通讯作者：
Siomi, Mikiko C.