MLL2 Is Required in Oocytes for Bulk Histone 3 Lysine 4 Trimethylation and Transcriptional Silencing
MLL2 Is Required in Oocytes for Bulk Histone 3 Lysine 4 Trimethylation and Transcriptional Silencing
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DOI：
10.1371/journal.pbio.1000453
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发表时间：
2010-08-01
期刊：
影响因子：
9.8
通讯作者：
Matzuk, Martin M.
中科院分区：
文献类型：
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作者：
Andreu-Vieyra, Claudia V.;Chen, Ruihong;Matzuk, Martin M.
在配子发生和植入前发育期间，哺乳动物表观基因组被重编程以在外胚层中建立多能性。在这里，我们表明，组蛋白3赖氨酸4（H3 K4）甲基转移酶，MLL 2，控制大多数的启动子特异性染色质修饰，H3 K4 me 3，在卵子发生和早期发育。使用条件性基因敲除突变和亚型模型，我们表明，MLL 2缺陷的卵母细胞的结果在无排卵和卵母细胞死亡，增加转录的p53，凋亡因子，和圈元素。MLL 2是（1）大量H3 K4 me 3而不是H3 K4 me 1所必需的，表明MLL 2控制大多数启动子，但单甲基化是由不同的H3 K4甲基转移酶调节的;（2）在减数分裂恢复之前的整体转录沉默，但不是伴随的核重组成包围的核仁（SN）染色质构型;（3）卵母细胞存活;（4）正常合子基因组激活。这些结果表明，MLL 2是自主需要在卵母细胞的生育能力，并暗示MLL 2有助于发生在受精前的表观遗传重编程。我们建议，一旦这项任务已经完成，MLL 2是不需要的，直到原肠胚和其他甲基转移酶负责散装H3 K4 me 3，从而揭示了一个意想不到的表观遗传控制开关之间的H3 K4甲基转移酶在发展过程中。
During gametogenesis and pre-implantation development, the mammalian epigenome is reprogrammed to establish pluripotency in the epiblast. Here we show that the histone 3 lysine 4 (H3K4) methyltransferase, MLL2, controls most of the promoter-specific chromatin modification, H3K4me3, during oogenesis and early development. Using conditional knockout mutagenesis and a hypomorph model, we show that Mll2 deficiency in oocytes results in anovulation and oocyte death, with increased transcription of p53, apoptotic factors, and lap elements. MLL2 is required for (1) bulk H3K4me3 but not H3K4me1, indicating that MLL2 controls most promoters but monomethylation is regulated by a different H3K4 methyltransferase; (2) the global transcriptional silencing that preceeds resumption of meiosis but not for the concomitant nuclear reorganization into the surrounded nucleolus (SN) chromatin configuration; (3) oocyte survival; and (4) normal zygotic genome activation. These results reveal that MLL2 is autonomously required in oocytes for fertility and imply that MLL2 contributes to the epigenetic reprogramming that takes place before fertilization. We propose that once this task has been accomplished, MLL2 is not required until gastrulation and that other methyltransferases are responsible for bulk H3K4me3, thereby revealing an unexpected epigenetic control switch amongst the H3K4 methyltransferases during development.