Human Molecular Genetics Advance Access originally published online on June 1, 2009
Human Molecular Genetics 2009 18(16):3066-3074; doi:10.1093/hmg/ddp248
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Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression
1 Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London WC1N 1EH, UK 2 Cancer Epigenetics and Biology Program, Catalan Institute of Oncology-IDIBELL, Gran Via s/n km 2.7, 08907L'Hospitalet, Barcelona, Spain 3 Institute of Molecular Genetics, CNRS, UMR-5535 and University of Montpellier I and II, 1919 Route de Mende, 34293 Montpellier, France 4 School of Health and Social Science, Middlesex University, Enfield EN3 4SA, UK
* To whom correspondence should be addressed. Tel: +34 932607500 ext. 3165; Fax: +34 932607219; Email: dmonk{at}iconcologia.net
Received January 29, 2009; Revised April 17, 2009; Accepted May 21, 2009
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.