GATA6-AS1 Regulates GATA6 Expression to Modulate Human Endoderm Differentiation

• Published in: Stem cell reports 2020-09, Vol.15 (3), p.694-705
• Main Authors: Yang, Jie, Lu, Pei, Li, Mao, Yan, Chenchao, Zhang, Tianzhe, Jiang, Wei
• Format: Article
• Language: English
• Subjects: GATA6; GATA6-AS1; human endoderm; human pluripotent stem cells; long noncoding RNA; SMAD2/3
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.07.014

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 identified GATA6-AS1, an lncRNA divergently transcribed from the GATA6 locus, is highly expressed during endoderm differentiation. Knockdown of GATA6-AS1 in human pluripotent stem cells has no influence on morphology and pluripotency; however, GATA6-AS1 depletion causes the deficiency of definitive endoderm differentiation. GATA6-AS1 positively regulates the expression of endoderm key factor GATA6. Further investigation shows GATA6-AS1 interacts 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 of GATA6-AS1, suggesting that GATA6 is the functional target of GATA6-AS1 during endoderm differentiation. Ultimately, our study reveals that GATA6-AS1 is necessary for human endoderm specification and reveals the underlying mechanism between GATA6-AS1 and GATA6. [Display omitted] •GATA6-AS1 is a lncRNA highly expressed in human endoderm with two isoforms•GATA6-AS1 controls human endoderm differentiation through regulating GATA6•GATA6-AS1 regulates GATA6, the functional target in endoderm differentiation•GATA6-AS1 is required for SMAD2/3-mediated GATA6 transcriptional activation In this study, Jiang and colleagues have identified an endoderm-expressed lncRNA, GATA6-AS1, which is necessary for definitive endoderm differentiation. GATA6-AS1 deletion causes the differentiation deficiency of human definitive endoderm. Further mechanistic study shows that GATA6-AS1 interacts with SMAD2/3 and recruits SMAD2/3 to activate GATA6 transcription, thus contributing to endoderm differentiation.