The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3.
The histone demethylase Jarid1b ensures faithful mouse development by protecting developmental genes from aberrant H3K4me3.
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DOI：
10.1371/journal.pgen.1003461
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Helin K
中科院分区：
文献类型：
--
作者：
Albert M;Schmitz SU;Kooistra SM;Malatesta M;Morales Torres C;Rekling JC;Johansen JV;Abarrategui I;Helin K
胚胎发育受转录因子和染色质相关蛋白的密切调控。H3 K4 me 3与活性转录相关，H3 K27 me 3与基因抑制相关，而两者的组合使发育所需的基因处于可塑状态。在这里，我们表明，删除H3 K4 me 2/3组蛋白去甲基化酶Jarid 1b（Kdm 5 b/Plu 1）的结果在主要的新生儿死亡，由于呼吸衰竭。Jarid 1b基因敲除胚胎有几个神经缺陷，包括颅神经紊乱，眼睛发育缺陷和露脑畸形的发生率增加。此外，与Jarid 1b和Polycomb靶基因的重叠一致，Jarid 1b敲除胚胎显示Polycomb突变体典型的同源异型骨骼转化，支持Polycomb蛋白和Jarid 1b之间的功能相互作用。为了了解Jarid 1b如何调节小鼠发育，我们对组蛋白修饰进行了全基因组分析，结果表明，在Jarid 1b敲除胚胎的早期胚胎发生过程中，编码发育调节因子的正常非活性基因获得了异常的H3 K4 me 3。随着胚胎发育的进行，H3 K4 me 3不断积累，导致Jarid 1b敲除大脑中Pax 6和Otx 2等神经主调节因子的表达增加。综上所述，这些结果表明，Jarid 1b通过保护发育基因免受活性组蛋白修饰的不当获取来调节小鼠发育。组蛋白修饰参与转录调控，从而影响细胞的身份、分化和发育。我们研究了组蛋白去甲基化酶Jarid 1b（Kdm 5 b/Plu 1），因为据报道它在几种人类癌症中高度表达，因此可能为抗癌治疗提供新的靶点。为了深入了解Jarid 1b的生理作用，我们已经产生了Jarid 1b敲除小鼠。我们发现，Jarid 1b的损失影响新生小鼠的生存，Jarid 1b是几个神经器官的忠实发展所需的。为了了解Jarid 1b如何调节胚胎发生，我们在全基因组范围内鉴定了H3 K4 me 3增加的基因以及发育过程中的Jarid 1b靶基因。在Jarid 1b基因敲除的胚胎中，神经发育的主调节因子以更高的水平表达，这强调了Jarid 1b在转录调节中的重要性。此外，我们扩展了以前的报告重叠Jarid 1b和Polycomb靶基因，以显示这一观察的功能相关性。我们的研究结果首次详细分析了Jarid 1b在正常发育中的作用，并为进一步研究评估Jarid 1b对肿瘤发生的贡献提供了基础。
Embryonic development is tightly regulated by transcription factors and chromatin-associated proteins. H3K4me3 is associated with active transcription and H3K27me3 with gene repression, while the combination of both keeps genes required for development in a plastic state. Here we show that deletion of the H3K4me2/3 histone demethylase Jarid1b (Kdm5b/Plu1) results in major neonatal lethality due to respiratory failure. Jarid1b knockout embryos have several neural defects including disorganized cranial nerves, defects in eye development, and increased incidences of exencephaly. Moreover, in line with an overlap of Jarid1b and Polycomb target genes, Jarid1b knockout embryos display homeotic skeletal transformations typical for Polycomb mutants, supporting a functional interplay between Polycomb proteins and Jarid1b. To understand how Jarid1b regulates mouse development, we performed a genome-wide analysis of histone modifications, which demonstrated that normally inactive genes encoding developmental regulators acquire aberrant H3K4me3 during early embryogenesis in Jarid1b knockout embryos. H3K4me3 accumulates as embryonic development proceeds, leading to increased expression of neural master regulators like Pax6 and Otx2 in Jarid1b knockout brains. Taken together, these results suggest that Jarid1b regulates mouse development by protecting developmental genes from inappropriate acquisition of active histone modifications. Histone modifications are involved in transcriptional regulation and thus affect cellular identity, differentiation, and development. We study the histone demethylase Jarid1b (Kdm5b/Plu1), as it has been reported to be highly expressed in several human cancers and therefore might present a novel target for anti-cancer therapies. To gain insights into the physiological role of Jarid1b, we have generated a Jarid1b knockout mouse. We show that loss of Jarid1b affects survival of newborn mice and that Jarid1b is required for the faithful development of several neural organs. To understand how Jarid1b regulates embryogenesis, we identified genes with increased H3K4me3 at a genome-wide scale as well as Jarid1b target genes during development. In Jarid1b knockout embryos, master regulators of neural development are expressed at higher levels, underscoring the importance of Jarid1b in transcriptional regulation. Furthermore, we extend previous reports of overlapping Jarid1b and Polycomb target genes to show the functional relevance of this observation. Our results provide the first detailed analysis of the role of Jarid1b in normal development and provide a basis for further studies evaluating the contribution of Jarid1b to tumorigenesis.
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