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J. Biol. Chem., Vol. 282, Issue 45, 33034-33042, November 9, 2007

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Developmental Pluripotency-associated 4 (DPPA4) Localized in Active Chromatin Inhibits Mouse Embryonic Stem Cell Differentiation into a Primitive Ectoderm Lineage^*

Hisaharu Masaki, Tomohiro Nishida, Shigetaka Kitajima, Kinji Asahina¹, and Hirobumi Teraoka

From the Departments of Pathological Biochemistry and Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan

Because embryonic stem (ES) cells can proliferate indefinitely in an undifferentiated state and differentiate into various cell types, ES cells are expected to be useful for cell replacement therapy and basic research on early embryogenesis. Although molecular mechanisms of ES cell self-renewal have been studied, many uncharacterized genes expressed in ES cells remain to be clarified. Developmental pluripotency associated 4 (Dppa4) is one such gene highly expressed in both ES cells and early embryos. Here, we investigated the role of Dppa4 in mouse ES cell self-renewal and differentiation. We generated Dppa4-overexpressing ES cells under the control of tetracycline. Dppa4 overexpression suppressed cell proliferation and formation of embryoid bodies and caused massive cell death in differentiating ES cells. Quantitative reverse transcription-PCR analysis showed that Dppa4 overexpression does not support ES cell self-renewal but partially inhibits ES cell differentiation. Suppression of Dppa4 expression by short hairpin RNA induced ES cell differentiation into a primitive ectoderm lineage. DPPA4 protein was localized in the ES cell nucleus associated with chromatin. Micrococcal nuclease digestion analysis and immunocytochemistry revealed that DPPA4 is associated with transcriptionally active chromatin. These findings indicate that DPPA4 is a nuclear factor associated with active chromatin and that it regulates differentiation of ES cells into a primitive ectoderm lineage.

Received for publication, April 17, 2007 , and in revised form, September 13, 2007.

^* This work was supported by Grants-in-Aid for Scientific Research 18390343 and 18048015 from the Ministry of Education, Culture, Sports, Science and Technology, Japan. 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.

¹ To whom correspondence should be addressed. Present address: Department of Pathology, Keck School of Medicine, University of Southern California. E-mail: asahina{at}usc.edu.

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