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首页> 外文期刊>Molecular and Cellular Biology >Epigenetic Regulation of Surfactant Protein A Gene (SP-A) Expression in Fetal Lung Reveals a Critical Role for Suv39h Methyltransferases during Development and Hypoxia
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Epigenetic Regulation of Surfactant Protein A Gene (SP-A) Expression in Fetal Lung Reveals a Critical Role for Suv39h Methyltransferases during Development and Hypoxia

机译：胎儿肺中表面活性蛋白A基因（SP-A）表达的表观遗传调控揭示了Suv39h甲基转移酶在发育和缺氧过程中的关键作用

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SP-A gene expression is developmentally regulated in fetal lung. Cyclic AMP (cAMP) induction of SP-A expression in human fetal lung type II cells is O2 dependent and is mediated by increased binding of TTF-1/Nkx2.1 and NF-κB to a critical response element (TBE). This is associated with increased acetylation and decreased methylation of H3K9 at the TBE. Using chromatin immunoprecipitation analysis of fetal lung between 15.5 and 19.0 days of gestation, we observed that the developmental induction of SP-A was associated with increased recruitment of TTF-1, NF-κB, PCAF, and CBP, as well as enhanced acetylation and decreased methylation of histone H3K9 at the TBE. Importantly, expression and TBE binding of the H3K9 methyltransferases, Suv39h1 and Suv39h2, was inversely correlated with the developmental upregulation of SP-A. In human fetal lung epithelial cells, Suv39H1 and Suv39H2 mRNA levels declined with cAMP induction of SP-A. Moreover, hypoxia, which inhibits cAMP stimulation of SP-A, markedly increased Suv39h1 and Suv39h2 binding to the TBE. Finally, short hairpin RNA knockdown of Suv39H1 or Suv39H2 in fetal lung epithelial cells repressed H3K9 methylation and greatly enhanced SP-A expression. Collectively, our findings suggest that Suv39H1 and Suv39H2 are key hypoxia-induced methyltransferases; their decline in fetal lung during late gestation is critical for epigenetic changes resulting in the developmental induction of SP-A.
机译：胚胎肺中 SP-A 基因的表达受到发育调控。人胚胎肺II型细胞中 SP-A 表达的循环AMP（cAMP）诱导是O 2 依赖性的，并且是通过TTF-1 / Nkx2.1结合力的增加而介导的NF-κB对关键反应元件（TBE）的影响。这与TBE处H3K9的乙酰化增加和甲基化降低有关。使用妊娠15.5天至19.0天之间胎儿肺的染色质免疫沉淀分析，我们观察到 SP-A 的发育诱导与TTF-1，NF-κB，PCAF和CBP募集增加有关，以及在TBE处增强组蛋白H3K9的乙酰化程度并降低其甲基化程度。重要的是，H3K9甲基转移酶Suv39h1和Suv39h2的表达和TBE结合与 SP-A的发育上调呈负相关。在人胎肺上皮细胞中，cAMP诱导后Suv39H1和Suv39H2 mRNA水平下降 SP-A 。此外，抑制cAMP刺激 SP-A 的缺氧显着增加了Suv39h1和Suv39h2与TBE的结合。最后，胎儿肺上皮细胞中Suv39H1或Suv39H2的短发夹RNA敲低抑制了H3K9甲基化并大大增强了 SP-A 表达。总的来说，我们的发现表明Suv39H1和Suv39H2是关键的缺氧诱导的甲基转移酶。它们在妊娠后期胎肺的下降对于表观遗传学变化至关重要，从而导致 SP-A 的发育诱导。

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