Journal
MOLECULAR THERAPY
Volume 25, Issue 10, Pages 2394-2403Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.06.028
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Funding
- National Natural Science Foundation of China [81401218, 81501250, 81125004, 31671567]
- National Basic Research Program of China [2013CB967404]
- Shanghai Natural Science Fund Project [14ZR1443800]
- Shanghai Municipal Health and Family Planning Commission [201640012]
- Fund for Outstanding Academic Leaders in Shanghai, China [2013-049]
- Health and Family Planning Commission, Hubei Province [WJ2017Z002]
- Shanghai Municipal Commission of Health and Family Planning [15GWZK0701]
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We aimed to determine the effect of YY1 expression on the expression profile of long noncoding RNAs (lncRNAs) in trophoblasts, and we studied the involvement of certain lncRNAs and YY1 in the pathogenesis of recurrent miscarriage (RM). RT2 lncRNA PCR arrays revealed that YY1 overexpression in trophoblasts significantly promoted the expression of the HOX transcript antisense RNA HOTAIR and demonstrated that HOTAIR expression was significantly lower in the RM trophoblasts than in control trophoblasts. Ectopic HOTAIR over expression and knockdown experiments revealed that it was a novel target of YY1. Bioinformatics analysis identified two YY1-binding sites in the HOTAIR promoter region, and chromatin immunoprecipitation (ChIP) analysis verified that YY1 binds directly to its promoter region. Interestingly, HOTAIR overexpression enhanced trophoblast invasion in an ex vivo explant culture model, while its knockdown repressed these effects. Furthermore, liquid chromatography-tandem mass spectrometry (LC-MS/MS) label-free quantitative proteomics screening revealed that HOTAIR overexpression activated phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling in trophoblasts. In an ex vivo explant culture model, HOTAIR overexpression effectively elevated matrix metalloproteinase 2 (MMP2) expression via the PI3K-AKT signaling pathway, enhancing trophoblast migration and invasion. These findings reveal a new regulatory pathway in which YY1 activates PI3K-AKT signaling via HOTAIR, promoting MMP2 expression, suggesting that HOTAIR is a potential therapeutic target for RM.
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