title: Silencing of cancer-germline genes in human preimplantation embryos: evidence for active de novo DNA methylation in stem cells.
abstract: Several human germline-specific genes rely principally on DNA methylation for repression in somatic tissues. Many of these genes, including MAGEA1, were qualified as cancer-germline (CG), as they become activated in tumors, where losses of DNA methylation are common. The developmental stage at which CG genes acquire DNA methylation marks is unknown. Here, we show that in human preimplantation embryos, transcription of CG genes increases up to the morula stage, and then decreases dramatically in blastocysts, suggesting that CG gene silencing occurs in blastocyst stem cells. Consistently, transfection studies with MAGEA1 constructs in embryonal carcinoma (EC) cells, which represent a malignant surrogate of blastocyst-derived stem cells, revealed active repression and marked de novo methylation of MAGEA1 transgenes in these cells. Active repression of the endogenous MAGEA1 gene in human EC cells was evidenced by its rapid re-silencing following prior induction with a DNA methylation inhibitor. Moreover, de novo DNA methyltransferases DNMT3A and DNMT3B appeared to contribute to the silencing of MAGEA1 and other CG genes in EC cells. Altogether our data indicate that CG genes like MAGEA1 are programmed for repression in the blastocyst, and suggest that de novo DNA methylation is a key event in this process.
authors.affiliation: Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Axelle
authors.initials: A
authors.lastname: Loriot
authors.forename: Grégory K
authors.initials: GK
authors.lastname: Parvizi
authors.forename: Sven
authors.initials: S
authors.lastname: Reister
authors.forename: Charles
authors.initials: C
authors.lastname: De Smet
mesh_terms: D001755:Blastocyst / Q000378:metabolism*; D045744:Cell Line, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D020868:Gene Silencing; D052138:Genes, Neoplasm; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D058950:Melanoma-Specific Antigens / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D058950:Melanoma-Specific Antigens; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C072011:MAGEA1 protein, human