Research article

Expression of BLIMP1/PRMT5 and concurrent histone H2A/H4 arginine 3 dimethylation in fetal germ cells, CIS/IGCNU and germ cell tumors

Dawid Eckert^{* 1} , Katharina Biermann^{* 2} , Daniel Nettersheim¹ , Ad JM Gillis⁵ , Klaus Steger³ , Hans-Martin Jäck⁴ , Annette M Müller² , Leendert HJ Looijenga⁵ and Hubert Schorle¹

¹Department of Developmental Pathology, Institute of Pathology, University of Bonn, Germany

²Institute of Pathology, University of Bonn, Germany

³Department of Urology and Pediatric Urology, University of Giessen, Germany, Institute of Pathology, University of Giessen, Germany

⁴Division of Molecular Immunology, Nikolaus-Fiebiger-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany

⁵Department of Pathology Erasmus MC-University Medical Center Rotterdam (Daniel den Hoed Cancer Center) Josephine Nefkens Institute, Rotterdam, the Netherlands

author email corresponding author email* Contributed equally

BMC Developmental Biology 2008, 8:106doi:10.1186/1471-213X-8-106

Published:	7 November 2008

Abstract

Background

Most testicular germ cell tumors arise from intratubular germ cell neoplasia unclassified (IGCNU, also referred to as carcinoma in situ), which is thought to originate from a transformed primordial germ cell (PGC)/gonocyte, the fetal germ cell. Analyses of the molecular profile of IGCNU and seminoma show similarities to the expression profile of fetal germ cells/gonocytes. In murine PGCs, expression and interaction of Blimp1 and Prmt5 results in arginine 3 dimethylation of histone H2A and H4. This imposes epigenetic modifications leading to transcriptional repression in mouse PGCs enabling them to escape the somatic differentiation program during migration, while expressing markers of pluripotency.

Results

In the present study, we show that BLIMP1 and PRMT5 were expressed and arginine dimethylation of histones H2A and H4 was detected in human male gonocytes at weeks 12–19 of gestation, indicating a role of this mechanism in human fetal germ cell development as well. Moreover, BLIMP1/PRMT5 and histone H2A and H4 arginine 3 dimethylation was present in IGCNU and most seminomas, while downregulated in embryonal carcinoma (EC) and other nonseminomatous tumors.

Conclusion

These data reveal similarities in marker expression and histone modification between murine and human PGCs. Moreover, we speculate that the histone H2A and H4 arginine 3 dimethylation might be the mechanism by which IGCNU and seminoma maintain the undifferentiated state while loss of these histone modifications leads to somatic differentiation observed in nonseminomatous tumors.