Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation.
Ultraconserved element uc.372 drives hepatic lipid accumulation by suppressing miR-195/miR4668 maturation.
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超保守元件uc.372通过抑制miR-195/miR4668成熟来驱动肝脏脂质积累
DOI：
10.1038/s41467-018-03072-8
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发表时间：
2018-02-09
影响因子：
16.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Guo J;Fang W;Sun L;Lu Y;Dou L;Huang X;Tang W;Yu L;Li J
超保守（uc）RNA是一类长链非编码RNA（lncRNA），在人类、小鼠和大鼠中是保守的，但uc RNA的生理意义和病理作用在很大程度上是未知的。在这里，我们发现uc.372在db/db小鼠、HFD喂养的小鼠和NAFLD患者的肝脏中上调。功能获得和功能丧失研究表明，uc.372通过促进脂肪生成驱动小鼠肝脏脂质蓄积。我们进一步证明uc.372与pri-miR-195/pri-miR-4668结合并抑制miR-195/miR-4668的成熟，以调节与脂质合成和摄取相关的基因的表达，包括ACC、FAS、SCD 1和CD 36。最后，我们确定uc.372位于胰岛素瘤相关2（INSM 2）基因的下游，该基因由上游转录因子1（USF 1）转录激活。我们的研究结果揭示了一种新的机制，uc.372通过抑制miR-195/miR-4668成熟来减轻miR-195/miR-4668介导的对功能性靶基因表达的抑制，从而驱动肝脏脂肪变性。超保守RNA是一类长的非编码RNA，其功能尚未确定。Guo及其同事在这里表明，一种超保守的RNA uc.372通过抑制抑制脂肪生成基因表达的miR-195/miR-4668的成熟来促进肝细胞内的脂肪生成和脂质积累。
Ultraconserved (uc) RNAs, a class of long non-coding RNAs (lncRNAs), are conserved across humans, mice, and rats, but the physiological significance and pathological role of ucRNAs is largely unknown. Here we show that uc.372 is upregulated in the livers of db/db mice, HFD-fed mice, and NAFLD patients. Gain-of-function and loss-of-function studies indicate that uc.372 drives hepatic lipid accumulation in mice by promoting lipogenesis. We further demonstrate that uc.372 binds to pri-miR-195/pri-miR-4668 and suppresses maturation of miR-195/miR-4668 to regulate expression of genes related to lipid synthesis and uptake, including ACC, FAS, SCD1, and CD36. Finally, we identify that uc.372 is located downstream of the insulinoma-associated 2 (INSM2) gene that is transcriptionally activated by upstream transcription factor 1 (USF1). Our findings reveal a novel mechanism by which uc.372 drives hepatic steatosis through inhibition of miR-195/miR-4668 maturation to relieve miR-195/miR-4668-mediated suppression of functional target gene expression. Ultraconserved RNAs are a class of long non-coding RNAs whose functions are yet to be identified. Here Guo and colleagues show that an ultraconserved RNA uc.372 promotes lipogenesis and lipid accumulation within the hepatocytes by suppressing the maturation of miR-195/miR-4668 that inhibits lipogenic gene expression.
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DOI：
10.1002/hep.28283
发表时间：
2016-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Goffredo M;Caprio S;Feldstein AE;D'Adamo E;Shaw MM;Pierpont B;Savoye M;Zhao H;Bale AE;Santoro N
通讯作者：
Santoro N
影响因子：
14.9
作者：
Griffiths-Jones, S
通讯作者：
Griffiths-Jones, S
影响因子：
10.5
作者：
Dey BK;Pfeifer K;Dutta A
通讯作者：
Dutta A
影响因子：
48
作者：
Ebert, Margaret S.;Neilson, Joel R.;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.
DOI：
10.1073/pnas.1011098108
发表时间：
2011-01-11
影响因子：
11.1
作者：
Braconi, Chiara;Valeri, Nicola;Patel, Tushar
通讯作者：
Patel, Tushar