A long non-coding RNA GATA6-AS1 adjacent to GATA6 is required for cardiomyocyte differentiation from human pluripotent stem cells.
A long non-coding RNA GATA6-AS1 adjacent to GATA6 is required for cardiomyocyte differentiation from human pluripotent stem cells.
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DOI：
10.1096/fj.202000206r
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Xu C
中科院分区：
文献类型：
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作者：
Jha R;Li D;Wu Q;Ferguson KE;Forghani P;Gibson GC;Xu C
长链非编码RNA（lncRNA）在许多细胞过程中是至关重要的，但相对较少的已被证明可调节人类心肌细胞分化。在这里，我们证明了GATA 6反义RNA 1（GATA 6-AS 1）在人多能干细胞（hPSC）分化为心肌细胞中的重要作用。GATA 6-AS 1与心脏转录因子GATA 6相邻。我们发现，GATA 6-AS 1是核定位和短暂上调沿着GATA 6在心肌细胞分化的早期阶段。GATA 6-AS 1的敲除不影响未分化细胞的多能性，但抑制心肌细胞分化，如没有或很少跳动的心肌细胞和心肌细胞特异性蛋白的表达减少所示。在心脏诱导后，GATA 6-AS 1的敲低降低了GATA 6的表达，改变了Wnt信号传导基因的表达，并减少了中胚层的发育。对GATA 6-AS 1和GATA 6基因组区域之间的基因间隔区的进一步表征表明，GATA 6-AS 1和GATA 6的表达受基因间隔区内的双向启动子调控。GATA 6-AS 1和GATA 6在包括心脏在内的几种人体组织中共表达，类似于心肌细胞分化过程中GATA 6-AS 1和GATA 6的镜像表达模式。总之，这些发现揭示了lncRNA GATA 6-AS 1在控制人心肌细胞分化中的先前未被认识的功能性作用。
Long noncoding RNAs (lncRNAs) are crucial in many cellular processes, yet relative few have been shown to regulate human cardiomyocyte differentiation. Here, we demonstrate an essential role of GATA6 antisense RNA 1 (GATA6-AS1) in cardiomyocyte differentiation from human pluripotent stem cells (hPSCs). GATA6-AS1 is adjacent to cardiac transcription factor GATA6. We found that GATA6-AS1 was nuclear-localized and transiently upregulated along with GATA6 during the early stage of cardiomyocyte differentiation. Knockdown of GATA6-AS1 did not affect undifferentiated cell pluripotency but inhibited cardiomyocyte differentiation, as indicated by no or few beating cardiomyocytes and reduced expression of cardiomyocyte-specific proteins. Upon cardiac induction, knockdown of GATA6-AS1 decreased GATA6 expression, altered Wnt-signaling gene expression and reduced mesoderm development. Further characterization of the intergenic region between genomic regions of GATA6-AS1 and GATA6 indicated that the expression of GATA6-AS1 and GATA6 were regulated by a bidirectional promoter within the intergenic region. Consistently, GATA6-AS1 and GATA6 were co-expressed in several human tissues including the heart, similar to the mirror expression pattern of GATA6-AS1 and GATA6 during cardiomyocyte differentiation. Overall, these findings reveal a previously unrecognized and functional role of lncRNA GATA6-AS1 in controlling human cardiomyocyte differentiation.