Hata Kenichiro, Okano Masaki, Lei Hong, Li En
Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
Development. 2002 Apr;129(8):1983-93. doi: 10.1242/dev.129.8.1983.
Genomic imprinting is regulated by differential methylation of the paternal and maternal genome. However, it remains unknown how parental imprinting is established during gametogenesis. In this study, we demonstrate that Dnmt3L, a protein sharing homology with DNA methyltransferases, Dnmt3a and Dnmt3b, but lacking enzymatic activity, is essential for the establishment of maternal methylation imprints and appropriate expression of maternally imprinted genes. We also show that Dnmt3L interacts with Dnmt3a and Dnmt3b and co-localizes with these enzymes in the nuclei of transfected cells, suggesting that Dnmt3L may regulate genomic imprinting via the Dnmt3 family enzymes. Consistent with this model, we show that [Dnmt3a(-/-), Dnmt3b(+/-)] mice also fail to establish maternal methylation imprints. In addition, both Dnmt3a and Dnmt3L are required for spermatogenesis. Together, our findings suggest that Dnmt3L may cooperate with Dnmt3 family methyltransferases to carry out de novo methylation of maternally imprinted genes in oocytes.
基因组印记由父本和母本基因组的差异甲基化调控。然而，在配子发生过程中亲本印记是如何建立的仍不清楚。在本研究中，我们证明了Dnmt3L，一种与DNA甲基转移酶Dnmt3a和Dnmt3b具有同源性但缺乏酶活性的蛋白质，对于母本甲基化印记的建立和母本印记基因的适当表达至关重要。我们还表明，Dnmt3L与Dnmt3a和Dnmt3b相互作用，并与这些酶在转染细胞的细胞核中共定位，这表明Dnmt3L可能通过Dnmt3家族酶来调控基因组印记。与该模型一致，我们发现[Dnmt3a(-/-)，Dnmt3b(+/-)]小鼠也无法建立母本甲基化印记。此外，精子发生需要Dnmt3a和Dnmt3L两者。总之，我们的研究结果表明，Dnmt3L可能与Dnmt3家族甲基转移酶合作，对卵母细胞中母本印记基因进行从头甲基化。
