GATA6-AS1 Regulates GATA6 Expression to Modulate Human Endoderm Differentiation
GATA6-AS1 Regulates GATA6 Expression to Modulate Human Endoderm Differentiation
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GATA6-AS1 调节 GATA6 表达以调节人内胚层分化
DOI：
10.1016/j.stemcr.2020.07.014
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发表时间：
2020-07
影响因子：
5.9
通讯作者：
Wei Jiang
中科院分区：
文献类型：
--
作者：
Jie Yang;Pei Lu;Mao Li;Chenchao Yan;Tianzhe Zhang;Wei Jiang
转录组分析已经揭示了一系列在细胞分化过程中转录的长链非编码rna (lncRNA)，但lncRNA如何与已知的转录调控网络整合尚不清楚。在这里，我们利用人类最终内胚层分化作为模型系统，并破译lncRNA和关键转录因子之间的功能相互作用。我们已经鉴定出GATA6- as1，一个从GATA6位点发散转录的lncRNA，在内胚层分化过程中高度表达。低敲gata6 - as1对人多能干细胞的形态和多能性无影响；然而，gata6 - as1缺失导致最终内胚层分化不足。GATA6- as1正调控内胚层关键因子GATA6的表达。进一步研究表明，sgata6 - as1与SMAD2/3相互作用，激活GATA6的转录。此外，过表达GATA6能够弥补由于缺乏GATA6- as1而导致的内胚层分化缺陷，说明GATA6是内胚层分化过程中GATA6- as1的功能靶点。最终，我们的研究揭示了GATA6- as1是人类内胚层规范所必需的，并揭示了GATA6- as1和GATA6之间的潜在机制。
Transcriptome analysis has uncovered a series of long noncoding RNAs (lncRNAs) transcribed during cell differentiation, but how lncRNA is integrated with known transcriptional regulatory network is poorly understood. Here, we utilize human definitive endoderm differentiation as a model system and decipher the functional interaction between lncRNA and key transcriptional factor. We have identifiedGATA6-AS1, an lncRNA divergently transcribed from the GATA6 locus, is highly expressed during endoderm differentiation. Knockdown ofGATA6-AS1in human pluripotent stem cells has no influence on morphology and pluripotency; however,GATA6-AS1depletion causes the deficiency of definitive endoderm differentiation.GATA6-AS1positively regulates the expression of endoderm key factor GATA6. Further investigation showsGATA6-AS1interacts with SMAD2/3 and activates the transcription of GATA6. In addition, overexpression of GATA6 is able to rescue the defect of endoderm differentiation due to the absence ofGATA6-AS1, suggesting that GATA6 is the functional target ofGATA6-AS1during endoderm differentiation. Ultimately, our study reveals thatGATA6-AS1is necessary for human endoderm specification and reveals the underlying mechanism betweenGATA6-AS1and GATA6.
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