Open Access BASE2008

Cancer genes hypermethylated in human embryonic stem cells

Calvanese, Vicenzo; Horrillo, Angelica; Hmadcha, Abdelkrim; Suárez-Álvarez, Beatriz; Fernández, Agustín F; Lara, Ester; Casado, Sara; Menéndez, Pablo; Bueno, Clara; García-Castro, Javier; Rubio, Ruth; Lapunzina, Pablo; Alaminos Mingorance, Miguel; Borghese, Lodovica; Terstegge, Stefanie; Harrison, Neil J; Moore, Harry D; Brüstle, Oliver; López Larrea, Carlos; Andrews, Peter W; Soria, Bernat; Esteller, Manel; Fraga, Mario F

Open Access

Abstract

Developmental genes are silenced in embryonic stem cells by a bivalent histone-based chromatin mark. It has been proposed that this mark also confers a predisposition to aberrant DNA promoter hypermethylation of tumor suppressor genes (TSGs) in cancer. We report here that silencing of a significant proportion of these TSGs in human embryonic and adult stem cells is associated with promoter DNA hypermethylation. Our results indicate a role for DNA methylation in the control of gene expression in human stem cells and suggest that, for genes repressed by promoter hypermethylation in stem cells in vivo, the aberrant process in cancer could be understood as a defect in establishing an unmethylated promoter during differentiation, rather than as an anomalous process of de novo hypermethylation. ; This work was primarily supported by the European Union (LSHG-CT-2006-018739; ESTOOLS). MFF is funded by the Spanish Ramon & Cajal Programme and the Health Department of the Spanish Government (PI061267). The Cancer Epigenetics group at the CNIO is supported by the Health (FIS01-04) and Education and Science (I+D+I MCYT08-03, FU2004-02073/BMC and Consolider MEC09-05) Departments of the Spanish Government, the European Grant TRANSFOG LSHC-CT-2004-503438, and the Spanish Association Against Cancer (AECC). VC is a recipient of a Fellowship from the FPU Spanish Research Programme. CLL and BSA are supported by the Health Department of the Spanish Government (PI051707). The BACM is supported by the Consejería de Salud de la Junta de Andalucía (0029 and, 0030/2006 to PM) and, the Spanish Ministry of Health to PM (FIS PI070026). CB is supported by the International Jose Carreras Foundation against Leukemia (EDThomas-05) and the ISCIII (FIS 3+3 contract). The Institute of Reconstructive Neurobiology received additional funding from the DFG and the Hertie Foundation. BS, AbH and AnH are supported by the Fundación Progreso y Salud and Instituto de Salud Carlos III-Red Española de Terapia Celular (RD06/0010/0025 ). PWA, NH and HDM are also supported by the MRC.

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