Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development
Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development
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DOI：
10.1242/dev.02302
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发表时间：
2006-04-15
期刊：
影响因子：
4.6
通讯作者：
Stewart, AF
中科院分区：
文献类型：
--
作者：
Glaser, S;Schaft, J;Stewart, AF
表观遗传是指分裂细胞的子代保留在细胞分裂前确定的染色质状态的过程。研究得最为透彻的案例涉及异染色质染色体区域的遗传，而对于通过表观遗传机制进行的特定基因调控知之甚少。近期的证据表明，表观遗传的关键在于组蛋白3的赖氨酸4、9或27位点上核小体的甲基化。生物信息学显示，哺乳动物对于这些甲基化中的每一种都有几种酶，包括至少六种组蛋白3赖氨酸4甲基转移酶。为了寻找哺乳动物发育过程中基因特异性表观遗传调控的证据，我们研究了这六种酶中的一种——Mll2，利用小鼠中的一个多用途等位基因来确定其功能缺失的表型。Mll2的缺失减缓了生长，增加了细胞凋亡并延缓了发育，导致在胚胎发育到11.5天之前失败。通过嵌合体实验，我们证明了Mll2是细胞自主需要的。也观察到了基因特异性调控的证据。尽管Mox1和Hoxb1的表达模式能够正确建立，但在没有Mll2的情况下无法维持，而Wnt1和Otx2的表达则可以维持。Mll2的功能缺失表型不同于其姊妹基因Mll，并且它们在胚胎干细胞分化过程中调控不同的Hox复合基因。因此，这两个密切相关的表观遗传因子在发育过程中发挥不同的作用，并维持不同的基因表达模式。这表明其他表观遗传因子也调控特定的模式，并且发育需要表观遗传特异性的网络。
Epigenesis is the process whereby the daughters of a dividing cell retain a chromatin state determined before cell division. The best-studied cases involve the inheritance of heterochromatic chromosomal domains, and little is known about specific gene regulation by epigenetic mechanisms. Recent evidence shows that epigenesis pivots on methylation of nucleosomes at histone 3 lysines 4, 9 or 27. Bioinformatics indicates that mammals have several enzymes for each of these methylations, including at least six histone 3 lysine 4 methyltransferases. To look for evidence of gene-specific epigenetic regulation in mammalian development, we examined one of these six, Mll2, using a multipurpose allele in the mouse to ascertain the loss-of-function phenotype. Loss of Mll2 slowed growth, increased apoptosis and retarded development, leading to embryonic failure before E11.5. Using chimera experiments, we demonstrated that Mll2 is cell-autonomously required. Evidence for gene-specific regulation was also observed. Although Mox1 and Hoxb1 expression patterns were correctly established, they were not maintained in the absence of Mll2, whereas Wnt1 and Otx2 were. The Mll2 loss-of-function phenotype is different from that of its sister gene Mll, and they regulate different Hox complex genes during ES cell differentiation. Therefore, these two closely related epigenetic factors play different roles in development and maintain distinct gene expression patterns. This suggests that other epigenetic factors also regulate particular patterns and that development entails networks of epigenetic specificities.