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首页> 外文期刊>PLoS Genetics >Stage-Dependent and Locus-Specific Role of Histone Demethylase Jumonji D3 (JMJD3) in the Embryonic Stages of Lung Development
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Stage-Dependent and Locus-Specific Role of Histone Demethylase Jumonji D3 (JMJD3) in the Embryonic Stages of Lung Development

机译：组蛋白去甲基化酶Jumonji D3（JMJD3）在肺发育的胚胎阶段的阶段依赖性和基因座特异性作用

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Histone demethylases have emerged as important players in developmental processes. Jumonji domain containing-3 (Jmjd3) has been identified as a key histone demethylase that plays a critical role in the regulation of gene expression; however, the in vivo function of Jmjd3 in embryonic development remains largely unknown. To this end, we generated Jmjd3 global and conditional knockout mice. Global deletion of Jmjd3 induces perinatal lethality associated with defective lung development. Tissue and stage-specific deletion revealed that Jmjd3 is dispensable in the later stage of embryonic lung development. Jmjd3 ablation downregulates the expression of genes critical for lung development and function, including AQP-5 and SP-B . Jmjd3-mediated alterations in gene expression are associated with locus-specific changes in the methylation status of H3K27 and H3K4. Furthermore, Jmjd3 is recruited to the SP-B promoter through interactions with the transcription factor Nkx2.1 and the epigenetic protein Brg1. Taken together, these findings demonstrate that Jmjd3 plays a stage-dependent and locus-specific role in the mouse lung development. Our study provides molecular insights into the mechanisms by which Jmjd3 regulates target gene expression in the embryonic stages of lung development. Author Summary A chromosome in the eukaryotic nucleus is an organized package of DNA coiled around histone proteins. DNA contains genes and other nucleotide sequences as well as histone proteins including H1, H2A, H2B, H3, and H4. Gene expression is dynamically regulated by DNA and histone modifications, such as methylation and demethylation. The protein Jumonji domain containing-3 (Jmjd3) is a critical demethylase that regulates gene expression. Here, we found that Jmjd3 plays an important role in the regulation of mouse lung development. Global Jmjd3 deletion results in perinatal lethality that is associated with respiratory failure caused by defective lung development. Tissue and stage-specific deletion show that Jmjd3 is dispensable for mouse lung development in the later stages (after E9.5). Jmjd3 deficiency downregulates the expression of genes critical for lung development through interactions with specific transcription factors and epigenetic protein complexes. Our findings provide new insights into the role and molecular mechanism of action of Jmjd3 in embryonic lung development.
机译：组蛋白脱甲基酶已成为发展过程中的重要参与者。 Jumonji域包含3（Jmjd3）已被确定为关键的组蛋白去甲基化酶，在基因表达的调控中起着至关重要的作用。然而，Jmjd3在胚胎发育中的体内功能仍然是未知的。为此，我们生成了Jmjd3全局和条件敲除小鼠。 Jmjd3的整体删除诱导与缺陷的肺发育相关的围产期致死率。组织和阶段特定的删除显示Jmjd3在胚胎肺发育的后期是可有可无的。 Jmjd3消融下调了对肺发育和功能至关重要的基因的表达，包括AQP-5和SP-B。 Jmjd3介导的基因表达变化与H3K27和H3K4甲基化状态的基因座特异性变化有关。此外，Jmjd3通过与转录因子Nkx2.1和表观遗传蛋白Brg1相互作用而被募集到SP-B启动子。综上所述，这些发现证明Jmjd3在小鼠肺部发育中起阶段依赖性和基因座特异性作用。我们的研究为Jmjd3在肺发育的胚胎阶段调节靶基因表达的机制提供了分子见解。作者简介真核细胞中的一条染色体是缠绕在组蛋白周围的DNA的有组织的包裹。 DNA包含基因和其他核苷酸序列以及组蛋白，包括H1，H2A，H2B，H3和H4。基因表达受DNA和组蛋白修饰（例如甲基化和去甲基化）动态调节。包含3的Jumonji结构域蛋白（Jmjd3）是调节基因表达的关键脱甲基酶。在这里，我们发现Jmjd3在调节小鼠肺部发育中起重要作用。全球Jmjd3删除导致围产期致死率，这与肺发育不良引起的呼吸衰竭有关。组织和阶段特异性删除显示Jmjd3在后期阶段（E9.5之后）对于小鼠肺部发育是可有可无的。 Jmjd3缺乏症通过与特定转录因子和表观遗传蛋白复合物的相互作用下调了对肺发育至关重要的基因的表达。我们的发现为Jmjd3在胚胎肺发育中的作用和分子机制提供了新的见解。

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