Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation.
Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation.
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DOI：
10.1038/s41598-017-03152-7
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发表时间：
2017-06-14
影响因子：
4.6
通讯作者：
Zhou B
中科院分区：
文献类型：
--
作者：
Flodby P;Li C;Liu Y;Wang H;Rieger ME;Minoo P;Crandall ED;Ann DK;Borok Z;Zhou B
分化相关基因的表观遗传调控尚不清楚。我们之前报道了转录因子GATA6和Sp1与大鼠肺泡上皮I型（AT1）细胞特异性基因水通道蛋白-5 （Aqp5）的近端358 bp启动子/增强子（p358P/E）相互作用并激活。在本研究中，我们发现组蛋白去乙酰化酶（HDAC）抑制剂亚eroylanilide羟肟酸（SAHA）增加AQP5表达和sp1介导的p358P/E转录。HDAC3过表达抑制sp1介导的Aqp5激活，而HDAC3敲低增强Aqp5蛋白表达。敲低GATA6或转录共激活因子/组蛋白乙酰转移酶p300可降低AQP5的表达，而过表达p300可增强GATA6和Sp1对p358P/E的激活。GATA6过表达、SAHA处理或HDAC3敲低会增加小鼠Aqp5同源p358P/E区组蛋白H3 （H3）的乙酰化，但不会增加组蛋白H4 （H4）的乙酰化。HDAC3与Sp1结合，HDAC3的敲除增加了GATA6/Sp1、GATA6/p300和Sp1/p300的相互作用。这些结果表明，GATA6和HDAC3分别通过调控H3乙酰化/去乙酰化，通过与Sp1的竞争来控制Aqp5的转录，p300通过调节乙酰化和/或与GATA6/Sp1相互作用来调节Aqp5的转录。转录因子和组蛋白修饰之间的协同相互作用调节了肺泡上皮细胞转分化过程中Aqp5的表达，表明HDAC抑制剂可能通过促进AT1细胞表型的获得来增强修复。
Epigenetic regulation of differentiation-related genes is poorly understood. We previously reported that transcription factors GATA6 and Sp1 interact with and activate the rat proximal 358-bp promoter/enhancer (p358P/E) of lung alveolar epithelial type I (AT1) cell-specific gene aquaporin-5 (Aqp5). In this study, we found that histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) increased AQP5 expression and Sp1-mediated transcription of p358P/E. HDAC3 overexpression inhibited Sp1-mediated Aqp5 activation, while HDAC3 knockdown augmented AQP5 protein expression. Knockdown of GATA6 or transcriptional co-activator/histone acetyltransferase p300 decreased AQP5 expression, while p300 overexpression enhanced p358P/E activation by GATA6 and Sp1. GATA6 overexpression, SAHA treatment or HDAC3 knockdown increased histone H3 (H3) but not histone H4 (H4) acetylation within the homologous p358P/E region of mouse Aqp5. HDAC3 binds to Sp1 and HDAC3 knockdown increased interaction of GATA6/Sp1, GATA6/p300 and Sp1/p300. These results indicate that GATA6 and HDAC3 control Aqp5 transcription via modulation of H3 acetylation/deacetylation, respectively, through competition for binding to Sp1, and suggest that p300 modulates acetylation and/or interacts with GATA6/Sp1 to regulate Aqp5 transcription. Cooperative interactions among transcription factors and histone modifications regulate Aqp5 expression during alveolar epithelial cell transdifferentiation, suggesting that HDAC inhibitors may enhance repair by promoting acquisition of AT1 cell phenotype.