Alexander Katherine A, Wang Xu, Shibata Maho, Clark Andrew G, García-García María J
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Cell Rep. 2015 Nov 10;13(6):1194-1205. doi: 10.1016/j.celrep.2015.09.078. Epub 2015 Oct 29.
Genomic imprinting depends on the establishment and maintenance of DNA methylation at imprinting control regions. However, the mechanisms by which these heritable marks influence allele-specific expression are not fully understood. By analyzing maternal, zygotic, maternal-zygotic, and conditional Trim28 mutants, we found that the transcription factor TRIM28 controls genomic imprinting through distinct mechanisms at different developmental stages. During early genome-wide reprogramming, both maternal and zygotic TRIM28 are required for the maintenance of methylation at germline imprints. However, in conditional Trim28 mutants, Gtl2-imprinted gene expression was lost despite normal methylation levels at the germline IG-DMR. These results provide evidence that TRIM28 controls imprinting after early embryonic reprogramming through a mechanism other than the maintenance of germline imprints. Additionally, our finding that secondary imprints were hypomethylated in TRIM28 mutants uncovers a requirement of TRIM28 after genome-wide reprogramming for interpreting germline imprints and regulating DNA methylation at imprinted gene promoters.
基因组印记依赖于印记控制区域DNA甲基化的建立和维持。然而，这些可遗传标记影响等位基因特异性表达的机制尚未完全了解。通过分析母本、合子、母本-合子和条件性Trim28突变体，我们发现转录因子TRIM28在不同发育阶段通过不同机制控制基因组印记。在早期全基因组重编程过程中，母本和合子TRIM28对于维持种系印记的甲基化都是必需的。然而，在条件性Trim28突变体中，尽管种系IG-DMR处的甲基化水平正常，但Gtl2印记基因的表达却丧失了。这些结果证明，TRIM28在早期胚胎重编程后通过一种不同于维持种系印记的机制来控制印记。此外，我们发现在TRIM28突变体中二级印记发生了低甲基化，这揭示了全基因组重编程后TRIM28对于解读种系印记和调节印记基因启动子处的DNA甲基化的必要性。
