Stage-dependent and locus-specific role of histone demethylase Jumonji D3 (JMJD3) in the embryonic stages of lung development.
Stage-dependent and locus-specific role of histone demethylase Jumonji D3 (JMJD3) in the embryonic stages of lung development.
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DOI：
10.1371/journal.pgen.1004524
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发表时间：
2014-07
期刊：
影响因子：
4.5
通讯作者：
Wang RF
中科院分区：
文献类型：
--
作者：
Li Q;Wang HY;Chepelev I;Zhu Q;Wei G;Zhao K;Wang RF
组蛋白去甲基化酶已成为发育过程中的重要参与者。Jumonji domain containing-3（Jmjd 3）已被鉴定为在基因表达调控中起关键作用的关键组蛋白去甲基化酶;然而，Jmjd 3在胚胎发育中的体内功能在很大程度上仍然未知。为此，我们产生了Jmjd 3全局和条件性敲除小鼠。Jmjd 3的整体缺失诱导与肺发育缺陷相关的围产期致死率。组织和阶段特异性缺失表明，Jmjd 3是在胚胎肺发育的后期。Jmjd 3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。Jmjd 3介导的基因表达改变与H3 K27和H3 K4甲基化状态的位点特异性变化相关。此外，Jmjd 3通过与转录因子Nkx2.1和表观遗传蛋白Brg 1的相互作用被募集到SP-B启动子。总之，这些发现表明，Jmjd 3在小鼠肺发育中起着阶段依赖性和基因座特异性作用。我们的研究为Jmjd 3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。真核细胞核中的染色体是一个有组织的DNA包裹，盘绕在组蛋白周围。DNA包含基因和其他核苷酸序列以及组蛋白，包括H1，H2 A，H2 B，H3和H4。基因表达受到DNA和组蛋白修饰（例如甲基化和去甲基化）的动态调节。Jumonji domain containing-3（Jmjd 3）蛋白是调节基因表达的关键脱甲基酶。在这里，我们发现Jmjd 3在调节小鼠肺发育中起着重要作用。全球Jmjd 3缺失导致围产期死亡，这与肺发育缺陷引起的呼吸衰竭有关。组织和阶段特异性缺失表明，Jmjd 3在小鼠肺发育的后期（E9.5后）是不稳定的。jmjd 3缺陷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肺发育关键基因的表达。我们的研究结果为Jmjd 3在胚胎肺发育中的作用和分子机制提供了新的见解。
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. 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.
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