Hochedlinger K, Plath K.. Epigenetic reprogramming and induced pluripotency. Development 136: 509-523

Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Boston, MA 02114, USA.
Development (Impact Factor: 6.46). 03/2009; 136(4):509-23. DOI: 10.1242/dev.020867
Source: PubMed


The cloning of animals from adult cells has demonstrated that the developmental state of adult cells can be reprogrammed into that of embryonic cells by uncharacterized factors within the oocyte. More recently, transcription factors have been identified that can induce pluripotency in somatic cells without the use of oocytes, generating induced pluripotent stem (iPS) cells. iPS cells provide a unique platform to dissect the molecular mechanisms that underlie epigenetic reprogramming. Moreover, iPS cells can teach us about principles of normal development and disease, and might ultimately facilitate the treatment of patients by custom-tailored cell therapy.

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    • "Recent research showed that cooperative binding events are evolutionary much stronger conserved (G € oke et al., 2011; He et al., 2011; Kazemian et al., 2013) and show a greater impact on expression compared with individual binding events (Hemberg and Kreiman, 2011). Furthermore, they turned out to be driving regulators in essential eukaryotic control processes such as the cell cycle in yeast (Simon et al., 2001), body part formation in Drosophila (He et al., 2011; Kazemian et al., 2013) or mammalian cell fate determination (G € oke et al., 2011; Hochedlinger and Plath, 2009; Wilson et al., 2010). The understanding of this combinatorial interplay requires a paradigm shift from single key players to the coupled activity of many regulatory control elements. "
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    ABSTRACT: Motivation: Eukaryotic gene expression is controlled through molecular logic circuits that combine regulatory signals of many different factors. In particular, complexation of transcription factors (TFs) and other regulatory proteins is a prevailing and highly conserved mechanism of signal integration within critical regulatory pathways and enables us to infer controlled genes as well as the exerted regulatory mechanism. Common approaches for protein complex prediction that only use protein interaction networks, however, are designed to detect self-contained functional complexes and have difficulties to reveal dynamic combinatorial assemblies of physically interacting proteins.Results: We developed the novel algorithm DACO that combines protein–protein interaction networks and domain–domain interaction networks with the cluster-quality metric cohesiveness. The metric is locally maximized on the holistic level of protein interactions, and connectivity constraints on the domain level are used to account for the exclusive and thus inherently combinatorial nature of the interactions within such assemblies. When applied to predicting TF complexes in the yeast Saccharomyces cerevisiae, the proposed approach outperformed popular complex prediction methods by far. Furthermore, we were able to assign many of the predictions to target genes, as well as to a potential regulatory effect in agreement with literature evidence.Availability and implementation: A prototype implementation is freely available at volkhard.helms@bioinformatik.uni-saarland.deSupplementary information: Supplementary data are available at Bioinformatics online.
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    • "In this model specific epigenetic modifications are acquired as progenitor cells, depicted as marbles (Fig. 7.1), differentiate and commit to a specific cell fate, conceptualized in the figure as marbles rolling down into one of several valleys. This idea has been substantiated by experimental findings where it has been demonstrated that commitment of cells into specific differentiation pathways is associated with progressive epigenetic modifications (Hochedlinger and Plath, 2009). "
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    • "This appears to be true for naive ESCs derived from mice (Ficz et al., 2013) and may be useful as a diagnostic marker for naive cells from other species (Chan et al., 2013; Gafni et al., 2013). Expression of key pluripotency factors is associated with demethylation of these loci in PGCs, in early embryos, and during experimental reprogramming (Apostolou and Hochedlinger, 2013; Hochedlinger and Plath, 2009). However, global demethylation in PGCs is not associated with promiscuous transcription (Seisenberger et al., 2012), nor is promoter demethylation in 2i associated with transcriptional activation of demethylated genes (Ficz et al., 2013; Habibi et al., 2013). "
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    ABSTRACT: The inheritance of epigenetic marks, in particular DNA methylation, provides a molecular memory that ensures faithful commitment to transcriptional programs during mammalian development. Epigenetic reprogramming results in global hypomethylation of the genome together with a profound loss of memory, which underlies naive pluripotency. Such global reprogramming occurs in primordial germ cells, early embryos, and embryonic stem cells where reciprocal molecular links connect the methylation machinery to pluripotency. Priming for differentiation is initiated upon exit from pluripotency, and we propose that epigenetic mechanisms create diversity of transcriptional states, which help with symmetry breaking during cell fate decisions and lineage commitment.
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