Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline
Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline
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DOI：
10.1242/dev.081661
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发表时间：
2012-10-01
期刊：
影响因子：
4.6
通讯作者：
Meehan, Richard R.
中科院分区：
文献类型：
--
作者：
Hackett, Jamie A.;Reddington, James P.;Meehan, Richard R.
小鼠原始生殖细胞（PGCs）消除全局DNA甲基化（5mC）是PGC发育过程中发生的全面表观遗传重编程的一部分。5mC在维持稳定的基因沉默和转座因子（TE）的抑制中发挥重要作用，但目前尚不清楚DNA甲基化的广泛缺失如何影响PGCs的基因表达和TE抑制。利用一种新的表观遗传破坏和恢复筛选和遗传分析，我们确定了一组核心的种系特异性基因，这些基因完全依赖启动子DNA甲基化来启动和维持发育沉默。这些基因启动子似乎拥有一个特殊的染色质环境，当DNA甲基化沉默时，不会获得任何抑制性的H3K27me3、H3K9me2、H3K9me3或H4K20me3组蛋白修饰。有趣的是，这个甲基化依赖的亚群在抑制生殖细胞TE活性的基因中高度富集。我们发现生殖系基因组防御基因的发育调控机制涉及依赖dnmt3b的从头DNA甲基化。然后，在迁移（类似于E8.5）和迁移后（E10.5-11.5） PGCs中，这些基因在不同的全局表观遗传重编程事件中被谱系特异性启动子去甲基化激活。我们提出，参与基因组防御的基因主要受启动子DNA甲基化的发育调控，作为一种感觉机制，在全球5mC清除过程中，启动子DNA甲基化与TE激活的可能性相耦合，从而作为一种故障保险，确保TE抑制并维持种系基因组完整性。
Mouse primordial germ cells (PGCs) erase global DNA methylation (5mC) as part of the comprehensive epigenetic reprogramming that occurs during PGC development. 5mC plays an important role in maintaining stable gene silencing and repression of transposable elements (TE) but it is not clear how the extensive loss of DNA methylation impacts on gene expression and TE repression in developing PGCs. Using a novel epigenetic disruption and recovery screen and genetic analyses, we identified a core set of germline-specific genes that are dependent exclusively on promoter DNA methylation for initiation and maintenance of developmental silencing. These gene promoters appear to possess a specialised chromatin environment that does not acquire any of the repressive H3K27me3, H3K9me2, H3K9me3 or H4K20me3 histone modifications when silenced by DNA methylation. Intriguingly, this methylation-dependent subset is highly enriched in genes with roles in suppressing TE activity in germ cells. We show that the mechanism for developmental regulation of the germline genome-defence genes involves DNMT3B-dependent de novo DNA methylation. These genes are then activated by lineage-specific promoter demethylation during distinct global epigenetic reprogramming events in migratory (similar to E8.5) and post-migratory (E10.5-11.5) PGCs. We propose that genes involved in genome defence are developmentally regulated primarily by promoter DNA methylation as a sensory mechanism that is coupled to the potential for TE activation during global 5mC erasure, thereby acting as a failsafe to ensure TE suppression and maintain genomic integrity in the germline.