Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotency
- Marc Friedli1,
- Priscilla Turelli1,
- Adamandia Kapopoulou1,
- Benjamin Rauwel1,
- Nathaly Castro-Díaz1,
- Helen M. Rowe1,5,
- Gabriela Ecco1,
- Carmen Unzu2,
- Evarist Planet1,
- Angelo Lombardo3,
- Bastien Mangeat4,
- Barbara E. Wildhaber2,
- Luigi Naldini3 and
- Didier Trono1
- 1School of Life Sciences and “Frontiers in Genetics” National Program, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland;
- 2Pediatric Surgery Laboratory, Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland;
- 3San Raffaele Telethon Institute for Gene Therapy and Vita Salute San Raffaele University, 20132 Milan, Italy;
- 4Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Corresponding author: didier.trono{at}epfl.ch
Abstract
Endogenous retroelements (EREs) account for about half of the mouse or human genome, and their potential as insertional mutagens and transcriptional perturbators is suppressed by early embryonic epigenetic silencing. Here, we asked how ERE control is maintained during the generation of induced pluripotent stem cells (iPSCs), as this procedure involves profound epigenetic remodeling. We found that all EREs tested were markedly up-regulated during the reprogramming of either mouse embryonic fibroblasts, human CD34+ cells, or human primary hepatocytes. At the iPSC stage, EREs of some classes were repressed, whereas others remained highly expressed, yielding a pattern somewhat reminiscent of that recorded in embryonic stem cells. However, variability persisted between individual iPSC clones in the control of specific ERE integrants. Both during reprogramming and in iPS cells, the up-regulation of specific EREs significantly impacted on the transcription of nearby cellular genes. While transcription triggered by specific ERE integrants at highly precise developmental stages may be an essential step toward obtaining pluripotent cells, the broad and unspecific unleashing of the repetitive genome observed here may contribute to the inefficiency of the reprogramming process and to the phenotypic heterogeneity of iPSCs.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.172809.114.
- Received January 21, 2014.
- Accepted May 23, 2014.
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