Establishment of paternal methylation imprint at the H19/Igf2 imprinting control region.
Establishment of paternal methylation imprint at the H19/Igf2 imprinting control region.
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DOI：
10.1126/sciadv.adi2050
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发表时间：
2023-09-08
期刊：
影响因子：
13.6
通讯作者：
Szabó PE
中科院分区：
文献类型：
--
作者：
Liao J;Song S;Gusscott S;Fu Z;VanderKolk I;Busscher BM;Lau KH;Brind'Amour J;Szabó PE
绝缘体模型解释了体细胞中H19和Igf2印迹结构域的工作原理，其中Igf2启动子与其增强子的绝缘发生在母体遗传的未甲基化染色体中，而不是父系遗传的甲基化等位基因中。在雄性种系中，将父本甲基化印记建立到印迹控制区（ICR）的分子机制尚不清楚。我们利用小鼠遗传学测试了促孕激素特异性低水平转录在这一过程中的功能。当转录在ICR的入口点停止时，父本印记的建立是异常的。生殖系上皮化持续进入体细胞父系等位基因，导致胎儿器官Igf2减少，胎儿生长减慢，与绝缘子模型和胰岛素样生长因子2 （Igf2）作为胎儿生长因子的作用一致。这些结果共同支持了广泛的低水平转录通过H19/Igf2 ICR在雄性种系中建立父本甲基化印记的作用，这对银罗素综合征具有启示意义。遗传实验发现，父系印记的建立需要广泛的低水平转录。
The insulator model explains the workings of the H19 and Igf2 imprinted domain in the soma, where insulation of the Igf2 promoter from its enhancers occurs by CTCF in the maternally inherited unmethylated chromosome but not the paternally inherited methylated allele. The molecular mechanism that targets paternal methylation imprint establishment to the imprinting control region (ICR) in the male germline is unknown. We tested the function of prospermatogonia-specific broad low-level transcription in this process using mouse genetics. Paternal imprint establishment was abnormal when transcription was stopped at the entry point to the ICR. The germline epimutation persisted into the paternal allele of the soma, resulting in reduced Igf2 in fetal organs and reduced fetal growth, consistent with the insulator model and insulin-like growth factor 2 (IGF2)’s role as fetal growth factor. These results collectively support the role of broad low-level transcription through the H19/Igf2 ICR in the establishment of its paternal methylation imprint in the male germ line, with implications for Silver-Russell syndrome. Genetic experiments find that paternal imprint establishment requires broad low-level transcription in prospermatogonia.
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