Human Molecular Genetics Advance Access published online on August 17, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm216
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Sequence-based bioinformatic prediction and QUASEP identify genomic imprinting of the KCNK9 potassium channel gene in mouse and human
1 Max-Delbrueck-Center for Molecular Medicine, D-13125 Berlin, Germany 2 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, United Kingdom 3 Franz Volhard Clinic, Charité, University Medical School, D-13122 Berlin, Germany 4 Institute of Human Genetics, Johannes Gutenberg University, D-55131 Mainz, Germany 5 Cologne Center for Genomics and Institute for Genetics, University of Cologne, D-50674 Cologne, Germany
* Correspondence to: Dr. Ulrich Zechner, Institute of Human Genetics, Johannes Gutenberg University Mainz, Langenbeckstraße 1, D-55131 Mainz, Germany. Phone: +49-6131-17-5850, Fax: +49-6131-17-5689, E-mail: zechner{at}humgen.klinik.uni-mainz.de
Received June 12, 2007; Revised July 19, 2007; Accepted July 30, 2007
Genomic imprinting is the epigenetic marking of gene subsets resulting in monoallelic or predominant expression of one of the two parental alleles according to their parental origin. We describe the systematic experimental verification of a prioritized 16 candidate imprinted gene set predicted by sequence-based bioinformatic analyses. We used Quantification of Allele-Specific Expression by Pyrosequencing (QUASEP) and discovered maternal-specific imprinted expression of the Kcnk9 gene as well as strain-dependent preferential expression of the Rarres1 gene in E11.5 (C57BL/6 x Cast/Ei)F1 and informative (C57BL/6 x Cast/Ei) x C57BL/6 backcross mouse embryos. For the remaining 14 candidate imprinted genes, we observed biallelic expression. In adult mouse tissues, we found that Kcnk9 expression was restricted to the brain and also was maternal-specific. QUASEP analysis of informative human fetal brain samples further demonstrated maternal-specific imprinted expression of the human KCNK9 orthologue. The CpG islands associated with the mouse and human Kcnk9/KCNK9 genes were not differentially methylated but strongly hypomethylated. Thus, we speculate that mouse Kcnk9 imprinting may be regulated by the maternal germline differentially methylated region (DMR) in Peg13, an imprinted non-coding RNA gene in close proximity to Kcnk9 on distal mouse chromosome 15. Our data have major implications for the proposed role of Kcnk9 in neurodevelopment, apoptosis, and tumorigenesis, as well as for the efficiency of sequence-based bioinformatic predictions of novel imprinted genes.
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