Monk David, Arnaud Philippe, Frost Jennifer, Hills Frank A, Stanier Philip, Feil Robert, Moore Gudrun E
Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
Hum Mol Genet. 2009 Aug 15;18(16):3066-74. doi: 10.1093/hmg/ddp248. Epub 2009 Jun 1.
Genomic imprinting may have evolved not only to regulate fetal growth and development, but also behaviour. The mouse Grb10 gene provides a remarkable model to explore this idea because it shows paternal expression in brain, whereas in the placenta and most other embryonic tissues, expression is from the maternal allele. To assess the biological relevance of this reciprocal pattern of imprinting, we explored its conservation in humans. As in mice, we find the human GRB10 gene to be paternally expressed in brain. Maternal allele-specific expression is conserved only in the placental villous trophoblasts, an essential part of the placenta involved in nutrient transfer. All other fetal tissues tested showed equal expression from both alleles. These data suggest that the maternal GRB10 expression in placenta is evolutionarily important, presumably in the control of fetal growth. As in the mouse, the maternal transcripts originate from several kilobases upstream of the imprinting control region (ICR) of the domain, from a promoter region at which we find no allelic chromatin differences. The brain-specific paternal expression from the ICR shows mechanistic similarities with the mouse as well. This conserved CpG island is DNA-methylated on the maternal allele and is marked on the paternal allele by developmentally regulated bivalent chromatin, with the presence of both H3 lysine-4 and H3 lysine-27 methylation. The strong conservation of the opposite allelic expression in placenta versus brain supports the hypothesis that GRB10 imprinting evolved to mediate diverse roles in mammalian growth and behaviour.
基因组印记的进化可能不仅是为了调节胎儿的生长发育，还与行为有关。小鼠的Grb10基因提供了一个很好的模型来探讨这一观点，因为它在大脑中呈现父本表达，而在胎盘和大多数其他胚胎组织中，表达来自母本等位基因。为了评估这种相互印记模式的生物学相关性，我们研究了其在人类中的保守性。与小鼠一样，我们发现人类GRB10基因在大脑中也是父本表达。母本等位基因特异性表达仅在胎盘绒毛滋养层中保守，胎盘绒毛滋养层是胎盘参与营养物质转运的重要组成部分。所有其他测试的胎儿组织都显示两个等位基因的表达相等。这些数据表明，胎盘内母本GRB10的表达在进化上很重要，可能在胎儿生长的控制中发挥作用。与小鼠一样，母本转录本起源于该结构域印记控制区（ICR）上游数千个碱基处，来自一个我们未发现等位基因染色质差异的启动子区域。ICR的大脑特异性父本表达在机制上也与小鼠相似。这个保守的CpG岛在母本等位基因上发生DNA甲基化，在父本等位基因上由发育调控的二价染色质标记，同时存在H3赖氨酸-4和H3赖氨酸-27甲基化。胎盘与大脑中相反等位基因表达的强烈保守性支持了这样一种假设，即GRB10印记的进化是为了在哺乳动物的生长和行为中发挥多种作用。
