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J. Biol. Chem., Vol. 280, Issue 8, 6265-6268, February 25, 2005

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Multiple Retropseudogenes from Pluripotent Cell-specific Gene Expression Indicates a Potential Signature for Novel Gene Identification^*

Debleena Pain, Gung-Wei Chirn, Christopher Strassel¶, and Daniel M. Kemp||**

From the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and Functional Genomics, ^¶IK@N, and the ^||Diabetes & Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139

Oct4, Nanog, and Stella are transcription factors specifically expressed in embryonic stem (ES) cells and germ lineage cells that impart critical functions in the maintenance of pluripotency. Here, we report the excessive frequency and apparent selectivity of retrotransposition of ES cell-specific genes. Six highly homologous pseudogenes for Oct4, 10 for Nanog, and 16 for Stella were identified by nucleotide BLAST (basic local alignment sequence tool) searches against the respective gene mRNA transcripts. Of 15 non-ES cell-specific transcription factor genes, only one had a single pseudogene hit in our screen, emphasizing the apparent selectivity. We present a hypothesis whereby retrotransposition of ES or germ cell-specific genes may reflect an innate predisposition. This is based on the increased probability of germ-line transmission when retrotransposition occurs at a very early stage of development within cells known to contribute to the germ cell lineage. The parental genes for Nanog, Stella, and another embryonic gene, GDF3 are all located on chromosome 12p13 of the human genome, and on chromosome 6 in mouse. Here, we identified an Oct4 pseudogene at the same respective loci in both human and mouse genomes, suggesting functional relevance and indicative of epigenetic regulation. We tested whether the apparent susceptibility for ES cell-specific gene retrotransposition may be extrapolated to a more unified phenomenon, such that a bioinformatic approach may represent a potentially novel strategy for identification of genes with embryonic cell-specific functionality. A preliminary investigation indeed revealed a single gene, previously demonstrated to be responsible for multiple retropseudogenes via germ cell-specific expression in Xenopus.

Received for publication, December 16, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Diabetes & Metabolism Disease Area, Novartis Inst. for BioMedical Research, 100 Technology Square, Cambridge, MA 02139. Tel.: 617-817-0105; Fax: 617-871-7051; E-mail: Daniel.kemp{at}pharma.novartis.com.

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