TY - JOUR
T1 - NANOG promoter methylation and expression correlation during normal and malignant human germ cell development
AU - Nettersheim, Daniel
AU - Biermann, Katharina
AU - Gillis, Ad J M
AU - Steger, Klaus
AU - Looijenga, Leendert H J
AU - Schorle, Hubert
N1 - Funding Information:
This work was supported by a grant from the DFG to H.S. (Scho 503/9). We thank Dr. Janet Shipley (Institute of Cancer Research, Sutton, England) for the TCam-2 cells, Dr. Michiko Fukuda (The Burnham Institute, La Jolla, CA.) for the JKT-1 cells and Dr. F. Honecker (Hamburg University Medical Center, Department of Oncology/Hematology, Hamburg, Germany) for the EC cell line 2102EP.
PY - 2011/1
Y1 - 2011/1
N2 - Testicular germ cell tumors are the most frequent malignant tumors in young Caucasian males, with increasing incidence. The actual model of tumorigenesis is based on the theory that a block in maturation of fetal germ cells lead to formation of the intratubular germ cell neoplasia unclassified. Early fetal germ cells and undifferentiated germ cell tumors express pluripotency markers such as the transcription factor NANOG. It has been demonstrated, that epigenetic modifications such as promoter DNA-methylation is able to silence gene expression in normal and cancer cells. Here we show, that OCT3/4-SOX2 mediated expression of NANOG can be silenced by methylation of promoter CpG-sites. We found that global methylation of DNA decreased from fetal spermatogonia to mature sperm. In contrast, CpGs in the NANOG promoter were found hypomethylated in spermatogonia and hypermethylated in sperm. This selective repression might reflect the cells need to suppress pluripotency in order to prevent malignant transformation. Finally, methylation of CpGs in the NANOG promoter in germ cell tumors and derived cell lines correlated to differentiation state.
AB - Testicular germ cell tumors are the most frequent malignant tumors in young Caucasian males, with increasing incidence. The actual model of tumorigenesis is based on the theory that a block in maturation of fetal germ cells lead to formation of the intratubular germ cell neoplasia unclassified. Early fetal germ cells and undifferentiated germ cell tumors express pluripotency markers such as the transcription factor NANOG. It has been demonstrated, that epigenetic modifications such as promoter DNA-methylation is able to silence gene expression in normal and cancer cells. Here we show, that OCT3/4-SOX2 mediated expression of NANOG can be silenced by methylation of promoter CpG-sites. We found that global methylation of DNA decreased from fetal spermatogonia to mature sperm. In contrast, CpGs in the NANOG promoter were found hypomethylated in spermatogonia and hypermethylated in sperm. This selective repression might reflect the cells need to suppress pluripotency in order to prevent malignant transformation. Finally, methylation of CpGs in the NANOG promoter in germ cell tumors and derived cell lines correlated to differentiation state.
KW - Cell Differentiation/physiology
KW - Cell Line, Tumor
KW - CpG Islands/physiology
KW - DNA Methylation
KW - Gene Silencing
KW - Homeodomain Proteins/genetics
KW - Humans
KW - Male
KW - Nanog Homeobox Protein
KW - Neoplasms, Germ Cell and Embryonal/genetics
KW - Promoter Regions, Genetic
KW - Spermatogonia/metabolism
KW - Spermatozoa/metabolism
UR - http://www.scopus.com/inward/record.url?scp=78651259053&partnerID=8YFLogxK
U2 - 10.4161/epi.6.1.13433
DO - 10.4161/epi.6.1.13433
M3 - Article
C2 - 20930529
SN - 1559-2294
VL - 6
SP - 114
EP - 122
JO - Epigenetics
JF - Epigenetics
IS - 1
ER -