Pham N V, Nguyen M T, Hu J F, Vu T H, Hoffman A R
Medical Service and Geriatric Research Education and Clinical Center, VA Palo Alto Health Care System and Department of Medicine, Stanford University, Palo Alto, CA 94304, USA.
Brain Res. 1998 Nov 9;810(1-2):1-8. doi: 10.1016/s0006-8993(98)00783-5.
The human IGF2 and H19 genes are imprinted in most normal tissues. Alterations of genomic imprinting or loss of imprinting (LOI) have been observed in a number of malignant tumors. Although LOI has been linked to tumorigenesis, loss of IGF2 imprinting has also been observed in choroid plexus and leptomeninges in normal mouse brain. We have therefore analyzed the allelic expression of both IGF2 and H19 in human fetal brain and in different regions of human adult brain. In the brains of fetuses of 6-12 weeks gestation, both IGF2 and H19 were transcribed from both parental alleles. In contrast, strictly monoallelic expression of both IGF2 and H19 was observed in all other fetal tissues, suggesting a tissue-specific LOI in the central nervous system. In adult brain, LOI of IGF2 was region-specific. IGF2 was expressed from both parental alleles in the pons, but not in globus palludus, Raphe nucleus and hypothalamus. H19 expression was drastically reduced in adult brain compared to fetal brain, and was detectable only in the pons and globus palludus. In contrast to IGF2, the expression of H19 in adult pons was monoallelic. Examination of IGF2 promoter usage indicated predominant utilization of promoter P3 in all fetal and adult brain tissues. The LOI of IGF2 therefore reflects biallelic expression from the predominant promoter. IGF2 transcripts derived from the less abundant promoter P1, however, showed monoallelic expression in the adult pons. Our results suggest that IGF2 and H19 undergo ontogenetic changes in allelic expression and that there is dissociation of IGF2 and H19 imprinting in both fetal and adult human brain.
人类IGF2和H19基因在大多数正常组织中是印记基因。在许多恶性肿瘤中已观察到基因组印记改变或印记丢失（LOI）。尽管LOI与肿瘤发生有关，但在正常小鼠脑的脉络丛和软脑膜中也观察到IGF2印记丢失。因此，我们分析了IGF2和H19在人类胎儿脑和成人脑不同区域的等位基因表达。在妊娠6 - 12周胎儿的脑中，IGF2和H19均从双亲等位基因转录。相比之下，在所有其他胎儿组织中均观察到IGF2和H19严格的单等位基因表达，提示中枢神经系统存在组织特异性的LOI。在成人大脑中，IGF2的LOI具有区域特异性。IGF2在脑桥中从双亲等位基因表达，但在苍白球、中缝核和下丘脑中不表达。与胎儿脑相比，成人大脑中H19的表达大幅降低，仅在脑桥和苍白球中可检测到。与IGF2不同，成脑桥中H19的表达是单等位基因的。对IGF2启动子使用情况的检查表明，在所有胎儿和成人脑组织中主要使用启动子P3。因此，IGF2的LOI反映了主要启动子的双等位基因表达。然而，来自较不丰富的启动子P1的IGF2转录本在成人脑桥中显示单等位基因表达。我们的结果表明，IGF2和H19在等位基因表达上经历个体发育变化，并且在胎儿和成人脑中IGF2和H19印记存在解离。
