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Silencing of cancer-germline genes in human preimplantation embryos evidence for activede novoDNA methylation in stem cells

Silencing of cancer-germline genes in human preimplantation embryos evidence for activede novoDNA methylation in stem cells

Several human germline-specific genes rely principally on DNA methylation for repression in somatic tissues. Many of these genes, includingMAGEA1, 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 withMAGEA1constructs in embryonal carcinoma (EC) cells, which represent a malignant surrogate of blastocyst-derived stem cells, revealed active repression and markedde novomethylation ofMAGEA1transgenes in these cells. Active repression of the endogenousMAGEA1gene in human EC cells was evidenced by its rapid re-silencing following prior induction with a DNA methylation inhibitor. Moreover,de novoDNA methyltransferases DNMT3A and DNMT3B appeared to contribute to the silencing ofMAGEA1and other CG genes in EC cells. Altogether our data indicate that CG genes likeMAGEA1are programmed for repression in the blastocyst, and suggest thatde novoDNA methylation is a key event in this process.Human cancer-germline (CG) genes, including MAGEA1, become repressed in blastocysts. Embryonal carcinoma (EC) stem cells exert active repression of the MAGEA1promoter. MAGEA1repression in EC cells involves de novoDNA methylation..

Accession: 036274774

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