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Nucleic Acids Res. 2014 Aug;42(14):8914-27. doi: 10.1093/nar/gku591. Epub 2014 Jul 17.

ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.

Author information

1
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
2
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
3
Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
4
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK myriam.hemberger@babraham.ac.uk.

Abstract

Embryonic stem (ES) cells are in a dynamic equilibrium of distinct functional states, characterized by the heterogeneous expression of critical pluripotency factors and regulated by a spectrum of reversible histone modifications. Maintenance of this equilibrium is a hallmark of pluripotency. Here we find that the ADP-ribosyltransferases Parp1 and Parp7 play a critical role in safeguarding this state by occupying key pluripotency genes, notably Nanog, Pou5f1, Sox2, Stella, Tet1 and Zfp42, thereby protecting them from progressive epigenetic repression. In the absence of either Parp1 or Parp7, or upon inhibition of the ADP-ribosylating activity, ES cells exhibit a decrease in ground state pluripotency as they cannot maintain the typical heterogeneity characteristic of the metastable state. As a consequence, they display a higher propensity to differentiate. These findings place Parp1 and Parp7 at the genetic-epigenetic interface of pluripotency networks, fine-tuning the transcriptional heterogeneity and thereby determining the developmental plasticity of ES cells.

PMID:
25034692
PMCID:
PMC4132717
DOI:
10.1093/nar/gku591
[Indexed for MEDLINE]
Free PMC Article

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