The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation.
The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation.
复制标题
睾丸特异性因子CTCFL与H19印迹控制区甲基化中的蛋白甲基转移酶PRMT7合作。
DOI：
10.1371/journal.pbio.0040355
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发表时间：
2006-10
期刊：
影响因子：
9.8
通讯作者：
Shaw, Phillip
中科院分区：
文献类型：
--
作者：
Jelinic, Petar;Stehle, Jean-Christophe;Shaw, Phillip
由于表观遗传调控-DNA甲基化和组蛋白修饰，印记基因的表达仅限于单个亲本等位基因。IGF2/H19是一个相互印记的基因座，表现为父亲的Igf2和母亲的H19表达。它们的表达受位于这两个基因之间的父系甲基化印记控制区(ICR)的调控。尽管从头DNA甲基转移酶已被证明是建立ICR甲基化所必需的，但它们靶向该区域的机制仍不清楚。我们证明了CTCFL/Boris是一种ICR结合蛋白，与CTCF类似，在胚胎雄性生殖细胞发育过程中表达，与ICR甲基化的时间一致。PRMT7是一种与CTCFL相互作用的精氨酸甲基转移酶，在胚胎睾丸发育过程中也有表达。组蛋白H4的对称性二甲基精氨酸3是一种由PRMT7催化的修饰，在这一发育过程中在生殖细胞中积累。染色质免疫沉淀(ChIP)分析还发现，这种修饰的组蛋白在睾丸的H19ICR和Gtl2差异甲基化区域(DMR)染色质中都有丰富的表达。体外研究表明，CTCFL通过与组蛋白和PRMT7相互作用来刺激PRMT7的组蛋白甲基转移酶活性。最后，通过将编码CTCFL、PRMT7和从头DNA甲基转移酶DNMT3a、-b和-L的表达载体共注射到非洲爪哇卵母细胞中，证实了H19ICR的甲基化。这些结果提示CTCFL和PRMT7可能在男性生殖系印记基因甲基化中起作用。睾丸特异性因子CTCFL(也称为Boris)可以与精氨酸组蛋白甲基转移酶(PRMT7)协同作用，在印迹控制区诱导DNA从头开始甲基化。
Expression of imprinted genes is restricted to a single parental allele as a result of epigenetic regulation—DNA methylation and histone modifications. Igf2/H19 is a reciprocally imprinted locus exhibiting paternal Igf2 and maternal H19 expression. Their expression is regulated by a paternally methylated imprinting control region (ICR) located between the two genes. Although the de novo DNA methyltransferases have been shown to be necessary for the establishment of ICR methylation, the mechanism by which they are targeted to the region remains unknown. We demonstrate that CTCFL/BORIS, a paralog of CTCF, is an ICR-binding protein expressed during embryonic male germ cell development, coinciding with the timing of ICR methylation. PRMT7, a protein arginine methyltransferase with which CTCFL interacts, is also expressed during embryonic testis development. Symmetrical dimethyl arginine 3 of histone H4, a modification catalyzed by PRMT7, accumulates in germ cells during this developmental period. This modified histone is also found enriched in both H19 ICR and Gtl2 differentially methylated region (DMR) chromatin of testis by chromatin immunoprecipitation (ChIP) analysis. In vitro studies demonstrate that CTCFL stimulates the histone-methyltransferase activity of PRMT7 via interactions with both histones and PRMT7. Finally, H19 ICR methylation is demonstrated by nuclear co-injection of expression vectors encoding CTCFL, PRMT7, and the de novo DNA methyltransferases, Dnmt3a, -b and -L, in Xenopus oocytes. These results suggest that CTCFL and PRMT7 may play a role in male germline imprinted gene methylation. The testes-specific factor CTCFL (also called BORIS) can cooperate with the arginine histone methyltransferase (PRMT7) to induce de novo DNA methylation at an imprinting control region.